Methods and compositions for improving cognitive function

ABSTRACT

This invention relates to methods and compositions for treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, it relates to the use of inhibitors of synaptic vesicle glycoprotein 2A (SV2A), alone or in combination with valproate, in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof, including, without limitation, subjects having or at risk for age-related cognitive impairment.

This application claims the benefit of and priority from U.S.provisional patent application 61/794,909, filed Mar. 15, 2013, thecontents and disclosures of which are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

This invention relates to methods and compositions for improvingcognitive function by using a synaptic vesicle glycoprotein 2A (SV2A)inhibitor, alone or in combination with valproate. In particular, itrelates to the use of SV2A inhibitors alone or in combination withvalproate in treating cognitive impairment associated with centralnervous system (CNS) disorders in a subject in need or at risk thereof,including, without limitation, subjects having or at risk forage-related cognitive impairment, Mild Cognitive Impairment (MCI),amnestic MCI (aMCI), Age-Associated Memory Impairment (AAMI), AgeRelated Cognitive Decline (ARCD), dementia, Alzheimer's Disease (AD),prodromal AD, post traumatic stress disorder (PTSD), schizophrenia,bipolar disorder, amyotrophic lateral sclerosis (ALS),cancer-therapy-related cognitive impairment, mental retardation,Parkinson's disease (PD), autism, compulsive behavior, and substanceaddiction.

BACKGROUND OF THE INVENTION

Cognitive ability may decline as a normal consequence of aging or as aconsequence of a CNS disorder.

For example, a significant population of elderly adults experiences adecline in cognitive ability that exceeds what is typical in normalaging. Such age-related loss of cognitive function is characterizedclinically by progressive loss of memory, cognition, reasoning, andjudgment. Mild Cognitive Impairment (MCI), Age-Associated MemoryImpairment (AAMI), Age-Related Cognitive Decline (ARCD) or similarclinical groupings are among those related to such age-related loss ofcognitive function. According to some estimates, there are more than 16million people with AAMI in the U.S. alone (Barker et al., 1995), andMCI is estimated to affect 5.5-7 million in the U.S. over the age of 65(Plassman et al., 2008).

Cognitive impairment is also associated with other central nervoussystem (CNS) disorders, such as dementia, Alzheimer's Disease (AD),prodromal AD, post traumatic stress disorder (PTSD), schizophrenia,bipolar disorder (e.g., mania), amyotrophic lateral sclerosis (ALS),cancer-therapy-related cognitive impairment, mental retardation,Parkinson's disease (PD), autism, compulsive behavior, and substanceaddiction.

There is, therefore, a need for effective treatment of cognitiveimpairment associated with central nervous system (CNS) disorders and toimprove cognitive function in patients diagnosed with, for example,age-related cognitive impairment, MCI, amnestic MCI, AAMI, ARCD,dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stressdisorder (PTSD), schizophrenia, bipolar disorder (e.g., mania),amyotrophic lateral sclerosis, cancer-therapy-related cognitiveimpairment, mental retardation, Parkinson's disease (PD), autism,compulsive behavior, and substance addiction, and similar centralnervous system (CNS) disorders associated with cognitive impairment orat risk of developing them.

SUMMARY OF THE INVENTION

In accordance with a first aspect of the present invention, there isprovided a method for treating cognitive impairment or improvingcognitive function, delaying or slowing the progression of cognitiveimpairment, or reducing the rate of decline of cognitive function, in asubject suffering from cognitive impairment associated with a centralnervous system (CNS) disorder, or at risk thereof, the method comprisingthe step of administering to said subject a therapeutically effectiveamount of an SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof. In some embodiments ofthis aspect of the invention, the methods improve or treat cognitivefunction in said subject. In some embodiments of this aspect of theinvention, the methods delay or slow the progression of cognitiveimpairment in said subject. In some embodiments of this aspect of theinvention, the methods reduce the rate of decline of cognitive functionin said subject. In some embodiments of this aspect of the invention,the methods prevent or slow the progression of the cognitive impairmentassociated with said CNS disorder in said subject. In other embodimentsof this aspect of the invention, the methods alleviate, ameliorate, orslow the progression, of one or more symptoms associated with thecognitive impairment aspects of said CNS disorder in said subject.

In some embodiments of this aspect of the invention, the cognitiveimpairment is associated with age-related cognitive impairment, such asMild Cognitive Impairment (MCI), Age-Associated Memory Impairment(AAMI), Age Related Cognitive Decline (ARCD). In one embodiment of thisaspect of the invention, the MCI is amnestic MCI. In some embodiments ofthis aspect of the invention, the cognitive impairment is associatedwith dementia, Alzheimer's Disease (AD), prodromal AD, post traumaticstress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophiclateral sclerosis, cancer-therapy-related cognitive impairment, mentalretardation, Parkinson's disease, autism, compulsive behavior, orsubstance addiction. In one embodiment of this aspect of the invention,the subject that suffers such cognitive impairment is a human patient.

The SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof that is useful in the methods andcompositions of this aspect of the invention include those disclosed in,for example, U.S. patent application Ser. No. 12/580,464 (Pub. No.US-2010-0099735), U.S. patent application Ser. No. 13/287,531 (Pub. No.US-2012-0046336), U.S. patent application Ser. No. 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647(Pub. No. WO2010/044878), International Patent ApplicationPCT/US12/24556 (Pub. No. WO2012/109491), U.S. Patent Application61/105,847, U.S. Patent Application 61/152,631, U.S. Patent Application61/175,536, and U.S. Patent Application 61/441,251. However, any SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof may be used in the methods andcompositions of this aspect of the invention. In other embodiments, theSV2A inhibitor is selected from the group of SV2A inhibitors referred toin International Patent Applications WO2010/144712; WO2010/002869;WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692;WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Pat.Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692 or theirpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs. In other embodiments, the SV2A inhibitor is selected from thegroup consisting of levetiracetam, brivaracetam, and seletracetam orderivatives or analogs or pharmaceutically acceptable salts, hydrates,solvates, polymorphs or prodrugs thereof. In other embodiments, the SV2Ainhibitor is levetiracetam or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In other embodiments, the SV2A inhibitor isbrivaracetam or a derivative or an analog or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof. Inother embodiments, the SV2A inhibitor is seletracetam or a derivative oran analog or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof.

In other embodiments of this aspect of the invention, the SV2A inhibitoror the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof can be administered at doses as disclosed, for example,in U.S. patent application Ser. No. 12/580,464 (Pub. No.US-2010-0099735), U.S. patent application Ser. No. 13/287,531 (Pub. No.US-2012-0046336), U.S. patent application Ser. No. 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647(Pub. No. WO2010/044878), International Patent ApplicationPCT/US12/24556 (Pub. No. WO2012/109491), U.S. Patent Application61/105,847, U.S. Patent Application 61/152,631, U.S. Patent Application61/175,536, and U.S. Patent Application 61/441,251. In other embodimentsof this aspect of the invention, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of about 0.1 to 0.2mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg,or about 0.06 to 1.8 mg/kg, or about 2.0 to 4.0 mg/kg, or about 2.0 to3.0 mg/kg, or about 3.0 to 4.0 mg/kg, or about 0.2 to 0.4 mg/kg, orabout 0.2 to 0.3 mg/kg, or about 0.3 to 0.4 mg/kg, or about 0.001-5mg/kg, or about 0.001-0.5 mg/kg, or about 0.01-0.5 mg/kg. In someembodiments of this aspect of the invention, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of about 0.1-500 mg,0.1-350 mg, 0.7-350 mg, 3-300 mg, 3-150 mg, 3-110 mg, 7-70 mg, 70-350mg, 100-300 mg, or 125-250 mg; or about 0.0015-7 mg/kg, 0.0015-5 mg/kg,0.01-5 mg/kg, 0.05-4 mg/kg, 0.05-2 mg/kg, 0.05-1.5 mg/kg, 0.1-1 mg/kg,1-5 mg/kg, 1.5-4 mg/kg, or 1.8-3.6 mg/kg.

In accordance with a second aspect of the present invention, there isprovided a method for treating cognitive impairment or improvingcognitive function, delaying or slowing the progression of cognitiveimpairment, or reducing the rate of decline of cognitive function, in asubject suffering from cognitive impairment associated with a centralnervous system (CNS) disorder, or at risk thereof, the method comprisingthe step of administering to said subject a therapeutically effectiveamount of an SV2A inhibitor or its pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug in combination with valproate oran analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof.

In some embodiments of this aspect of the invention, the SV2A inhibitorand/or valproate are administered at doses that are subtherapeutic ascompared to the doses at which they are therapeutically effective whenadministered in the absence of the other.

In some embodiments of this aspect of the invention, the cognitiveimpairment is associated with age-related cognitive impairment, such asMild Cognitive Impairment (MCI), Age-Associated Memory Impairment(AAMI), Age Related Cognitive Decline (ARCD). In one embodiment of thisaspect of the invention, the MCI is amnestic MCI. In some embodiments ofthis aspect of the invention, the cognitive impairment is associatedwith dementia, Alzheimer's Disease (AD), prodromal AD, post traumaticstress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophiclateral sclerosis, cancer-therapy-related cognitive impairment, mentalretardation, Parkinson's disease, autism, compulsive behavior, orsubstance addiction. In one embodiment, the subject that suffers suchcognitive impairment is a human patient.

The SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof that is useful in the methods andcompositions of this aspect of the invention include those disclosed in,for example, U.S. patent application Ser. No. 12/580,464 (Pub. No.US-2010-0099735), U.S. patent application Ser. No. 13/287,531 (Pub. No.US-2012-0046336), U.S. patent application Ser. No. 13/370,253 (Pub. No.US-2012-0214859), International Patent Application PCT/US2009/005647(Pub. No. WO2010/044878), International Patent ApplicationPCT/US12/24556 (Pub. No. WO2012/109491), U.S. Patent Application61/105,847, U.S. Patent Application 61/152,631, U.S. Patent Application61/175,536, and U.S. Patent Application 61/441,251. However, any SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof may be used in the methods andcompositions of this aspect of the invention. In other embodiments, theSV2A inhibitor is selected from the group of SV2A inhibitors referred toin International Patent Applications WO2010/144712; WO2010/002869;WO2008/132139; WO2007/065595; WO2006/128693; WO2006/128692;WO2005/054188; WO2004/087658; WO2002/094787; WO2001/062726; U.S. Pat.Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692 or theirpharmaceutically acceptable salts, hydrates, solvates, polymorphs orprodrugs. In other embodiments, the SV2A inhibitor is selected from thegroup consisting of levetiracetam, brivaracetam, and seletracetam orderivatives or analogs or pharmaceutically acceptable salts, hydrates,solvates, polymorphs or prodrugs thereof. In other embodiments, the SV2Ainhibitor is levetiracetam or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In other embodiments, the SV2A inhibitor isbrivaracetam or a derivative or an analog or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof. Inother embodiments, the SV2A inhibitor is seletracetam or a derivative oran analog or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof.

In other embodiments of this aspect of the invention, the SV2A inhibitoror the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof that is administered in combination with valproate orits analog, derivative or pharmaceutically acceptable salt can beadministered at doses as disclosed, for example, in U.S. patentapplication Ser. No. 12/580,464 (Pub. No. US-2010-0099735), U.S. patentapplication Ser. No. 13/287,531 (Pub. No. US-2012-0046336), U.S. patentapplication Ser. No. 13/370,253 (Pub. No. US-2012-0214859),International Patent Application PCT/US2009/005647 (Pub. No.WO2010/044878), International Patent Application PCT/US12/24556 (Pub.No. WO2012/109491), U.S. Patent Application 61/105,847, U.S. PatentApplication 61/152,631, U.S. Patent Application 61/175,536, and U.S.Patent Application 61/441,251. In other embodiments of this aspect ofthe invention, the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof that isadministered in combination with valproate or its analog, derivative orpharmaceutically acceptable salt is administered at a daily dose ofabout 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.1 mg/kg to5 mg/kg, or about 0.05 mg/kg to 0.5 mg/kg. In other embodiments of thisaspect of the invention, the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof that isadministered in combination with valproate or its analog, derivative orpharmaceutically acceptable salt is administered at a daily dose of lessthan 7 mg/kg, less than 6 mg/kg, less than 5 mg/kg, less than 4 mg/kg,less than 3.6 mg/kg, less than 3 mg/kg, less than 2 mg/kg, less than 1.5mg/kg, less than 1.5 mg/kg, less than 1 mg/kg, less than 0.1 mg/kg, lessthan 0.05 mg/kg, less than 0.01 mg/kg, or less than 0.0015 mg/kg, or ata daily dose of 0.0015-5 mg/kg, 0.01-5 mg/kg, 0.05-4.0 mg/kg, 0.05-2mg/kg, 0.05-1.5 mg/kg, 0.1-1 mg/kg, 1-5 mg/kg, 1.5-4 mg/kg, or 1.8-3.6mg/kg.

In certain embodiments of this aspect of the invention, valproate or ananalog, derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof that is administered in combination withthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is administered at a daily dosesuch that the subject maintains a blood total valproate level of 0.5 to5 μg/ml plasma.

In other embodiments of this aspect of the invention, the SV2A inhibitoror its pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug and the valproate or its analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug are administeredsimultaneously, or sequentially, or in a single formulation or inseparate formulations packaged together. In other embodiments of thisaspect of the invention, the SV2A inhibitor or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug and thevalproate or its analog, derivative, pharmaceutically acceptable salt,hydrate, solvate, polymorph or prodrug are administered via differentroutes. As used herein, “combination” includes administration by any ofthese formulations or routes of administration.

In certain embodiments of this aspect of the invention, the combinedtreatment has a longer or improved therapeutic effect in the subjectthan is attained by administering valproate or a derivative or an analogor a pharmaceutically acceptable salt, hydrate, solvate, polymorph orprodrug thereof in the absence of the SV2A inhibitor or apharmaceutically acceptable salt, solvate, hydrate, or polymorph orprodrug thereof by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about10×.

In other embodiments of this aspect of the invention, the combinedtreatment has a longer or improved therapeutic effect in the subjectthan is attained by administering the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof in the absence of valproate or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about 10×.

In accordance with another aspect of the present invention, there isprovided a method of increasing the therapeutic index of valproate or aderivative or an analog or a pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof in a method of treating cognitiveimpairment associated with a central nervous system (CNS) disorder in asubject in need or at risk thereof, comprising administering an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof in combination with valproate or aderivative or an analog or a pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof to said subject.

In some embodiments of this aspect of the invention, the increase in thetherapeutic index of valproate or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof is greater than the therapeutic index of valproate or aderivative or an analog or a pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof when administered in the absenceof the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof by at least about 1.5×, or 2.0×,or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×,or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×,or greater than about 10×.

In accordance with another aspect of the present invention, there isprovided a method of increasing the therapeutic index of an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof in a method of treating a cognitiveimpairment associated with central nervous system (CNS) disorder in asubject in need or at risk thereof, comprising administering an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof in combination with valproate or aderivative or an analog or a pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof to said subject.

In some embodiments of this aspect of the invention, the increase in thetherapeutic index of the SV2A inhibitor or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug thereof is greater than thetherapeutic index of the SV2A inhibitor or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug thereof when administeredin the absence of valproate or a derivative or an analog or apharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof by at least about 1.5×, or 2.0×, or 2.5×, or 3.0×, or 3.5×, or4.0×, or 4.5×, or 5.0×, or 5.5×, or 6.0×, or 6.5×, or 7.0×, or 7.5×, or8.0×, or 8.5×, or 9.0×, or 9.5×, or 10×, or greater than about 10×.

In accordance with another aspect of the present invention, there isprovided a pharmaceutical composition comprising an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof. In certain embodiments of this aspect of the invention, theSV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof is present in an amount of 0.07-60mg, 0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-140 mg, 0.7-180 mg,125-240 mg, 3-50 mg, or 3-60 mg. In other embodiments of this aspect ofthe invention, the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug thereof is present in anamount of 0.05-35 mg, 0.1-500 mg, 0.1-350 mg, 0.7-350 mg, 3-300 mg,3-150 mg, 3-110 mg, 7-70 mg, 70-350 mg, 100-300 mg, or 125-250 mg.

In accordance with another aspect of this invention, there is provided apharmaceutical composition comprising an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof in combination with valproate or an analog, derivative,pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In some embodiments of this aspect of the invention,the SV2A inhibitor or the pharmaceutically acceptable salt thereof ispresent in an amount of 0.05-35 mg, 0.07-60 mg, 0.07-350 mg, 25-60 mg,25-125 mg, 50-250 mg, 5-15 mg, 5-30 mg, 5-140 mg, 0.7-180 mg, 125-240mg, 3-50 mg, or 0.07-50 mg, 3-60 mg, or about 0.1-500 mg, 0.1-350 mg,0.7-350 mg, 3-300 mg, 3-150 mg, 3-110 mg, 7-70 mg, 70-350 mg, 100-300mg, or 125-250 mg. In other embodiments, the amount of the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is less than 500 mg, less than 350 mg,less than 300 mg, less than 250 mg, less than 200 mg, less than 150 mg,less than 110 mg, less than 100 mg, less than 70 mg, less than 50 mg,less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg, lessthan 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, less than0.1 mg, less than 0.07 mg, or less than 0.05 mg.

In certain embodiments of the composition provided in the invention, thecomposition is in a solid form. In some embodiments, the composition isin a liquid form. In some embodiments, the composition is in an aqueoussolution. In some embodiments, the composition is in a suspension form.In some embodiments, the composition is in an extended release form, acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form. In someembodiments, the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is in an extendedrelease form, a controlled release form, a prolonged release form, asustained release form, a delayed release form, or a slow release form.In some embodiments, the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof in anextended release form (or a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form) is formulated together with valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in a single formulation. In someembodiments, the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in an extended releaseform (or a controlled release form, a prolonged release form, asustained release form, a delayed release form, or a slow release form)is formulated together with valproate or an analog, derivative,pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof are formulated in separate formulations, which may bepackaged together. In some of the above composition embodiments wherethe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is in an extended release form(or a controlled release form, a prolonged release form, a sustainedrelease form, a delayed release form, or a slow release form), valproateor an analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is also in an extended releaseform (or a controlled release form, a prolonged release form, asustained release form, a delayed release form, or a slow release form).In some of the above composition embodiments where the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form), valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is not in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments of the composition of the present invention, valproate or ananalog, derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments, valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof in anextended release form (or a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form) is formulated together with the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in a single formulation. In some embodiments, valproateor an analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form) and the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof are formulated in separate formulations,which may be packaged together. In some of the above compositionembodiments where valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is inan extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form), the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is alsoin an extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form). In some of the above embodiments where valproate oran analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is in an extended release form(or a controlled release form, a prolonged release form, a sustainedrelease form, a delayed release form, or a slow release form), the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is not in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments, the composition is in a unit dosage form. In someembodiments, the composition is in a capsule or tablet form. In someembodiments, the composition is for oral administration. In otherembodiments, the two components of the compositions are in separatedelivery forms packaged together.

In accordance with another aspect of the present invention, there isprovided a method for treating cognitive impairment or improvingcognitive function, delaying or slowing the progression of cognitiveimpairment, or reducing the rate of decline of cognitive function, in asubject suffering from cognitive impairment associated with a centralnervous system (CNS) disorder, or at risk thereof, the method comprisingthe step of administering to said subject a therapeutically effectiveamount of levetiracetam or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof. In some embodiments of thisaspect of the invention, the methods improve or treat cognitive functionin said subject. In some embodiments of this aspect of the invention,the methods delay or slow the progression of cognitive impairment insaid subject. In some embodiments of this aspect of the invention, themethods reduce the rate of decline of cognitive function in saidsubject. In some embodiments of this aspect of the invention, themethods prevent or slow the progression of the cognitive impairmentassociated with said CNS disorder in said subject. In other embodimentsof this aspect of invention, the methods alleviate, ameliorate, or slowthe progression, of one or more symptoms associated with the cognitiveimpairment aspects of said CNS disorder in said subject.

In some embodiments of this aspect of the invention, the cognitiveimpairment is associated with age-related cognitive impairment, such asMild Cognitive Impairment (MCI), Age-Associated Memory Impairment(AAMI), Age Related Cognitive Decline (ARCD). In one embodiment of thisaspect of the invention, the MCI is amnestic MCI. In some embodiments ofthis aspect of the invention, the cognitive impairment is associatedwith dementia, Alzheimer's Disease (AD), prodromal AD, post traumaticstress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophiclateral sclerosis, cancer-therapy-related cognitive impairment, mentalretardation, Parkinson's disease, autism, compulsive behavior, orsubstance addiction. In one embodiment, the subject that suffers suchcognitive impairment is a human patient.

In certain embodiments of this aspect of the invention, thelevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of about 1to 2 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, orabout 0.6 to 1.8 mg/kg, or about 2.0 to 3.0 mg/kg, or about 3.0 to 4.0mg/kg, or about 2.0 to 4.0 mg/kg, or about 0.1-5 mg/kg, or about 70 to140 mg, or about 7 to 180 mg, or about 25-180 mg, or about 40 to 130 mg,or about 140 to 300 mg, or about 200 to 300 mg, or about 140 to 200 mg,or about 7-350 mg, 70-350 mg, 100-300 mg, or 125-250 mg, or about 0.1-5mg/kg, 1-5 mg/kg, 1.5-4 mg/kg, or 1.8-3.6 mg/kg.

In certain embodiments of this aspect of the invention, thelevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose accordingto one of the daily dose ranges indicated as “+” listed in Table 1 orTable 2. In some embodiments, the levetiracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereofadministered is in an extended release form, a controlled release form,a prolonged release form, a sustained release form, a delayed releaseform, or a slow release form. In some embodiments, the levetiracetam ora pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof administered is administered once or twice daily.

In accordance with another aspect of the present invention, there isprovided a method for treating cognitive impairment or improvingcognitive function, delaying or slowing the progression of cognitiveimpairment, or reducing the rate of decline of cognitive function, in asubject suffering from cognitive impairment associated with a centralnervous system (CNS) disorder, or at risk thereof, the method comprisingthe step of administering to said subject a therapeutically effectiveamount of brivaracetam or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof. In some embodiments of thisaspect of the invention, the methods improve or treat cognitive functionin said subject. In some embodiments of this aspect of the invention,the methods delay or slow the progression of cognitive impairment insaid subject. In some embodiments of this aspect of the invention, themethods reduce the rate of decline of cognitive function in saidsubject. In some embodiments of this aspect of the invention, themethods prevent or slow the progression of the cognitive impairmentassociated with said CNS disorder in said subject. In other embodimentsof this aspect of invention, the methods alleviate, ameliorate, or slowthe progression, of one or more symptoms associated with the cognitiveimpairment aspects of said CNS disorder in said subject.

In some embodiments of this aspect of the invention, the cognitiveimpairment is associated with age-related cognitive impairment, such asMild Cognitive Impairment (MCI), Age-Associated Memory Impairment(AAMI), Age Related Cognitive Decline (ARCD). In one embodiment of thisaspect of the invention, the MCI is amnestic MCI. In some embodiments ofthis aspect of the invention, the cognitive impairment is associatedwith dementia, Alzheimer's Disease (AD), prodromal AD, post traumaticstress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophiclateral sclerosis, cancer-therapy-related cognitive impairment, mentalretardation, Parkinson's disease, autism, compulsive behavior, orsubstance addiction. In one embodiment, the subject that suffers suchcognitive impairment is a human patient.

In certain embodiments of this aspect of the invention, the brivaracetamor the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of about 0.1 to 0.2mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.04 to 2.5 mg/kg, or about0.06 to 1.8 mg/kg, or about 0.2 to 0.4 mg/kg, or about 7 to 15 mg, orabout 0.7 to 180 mg, or about 2.5 to 180 mg, or about 4.0 to 130 mg, orabout 14 to 30 mg. In other embodiments, the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of about 0.1-350 mg,0.7-350 mg, 3-300 mg, 3-150 mg, 3-110 mg, or 7-70 mg; or 0.0015-5 mg/kg,0.01-5 mg/kg, 0.05-4.0 mg/kg, 0.05-2 mg/kg, 0.05-1.5 mg/kg, or 0.1-1mg/kg.

In certain embodiments of this aspect of the invention, the brivaracetamor the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of at least 0.1 mg, 0.5mg, 0.75 mg, 1.0 mg, 1.5 mg, or 2.0 mg; but no more than a daily dose of2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg. In otherembodiments, the brivaracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015mg/kg, 0.02 mg/kg, or 0.03 mg/kg; but no more than a daily dose of 0.5mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05mg/kg, or 0.04 mg/kg.

In certain embodiments of this aspect of the invention, the brivaracetamor the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose according to one of thedaily dose ranges indicated as “+” listed in Tables 3-6. For example,the brivaracetam or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof may be administered at a dailydose of 0.1-35 mg, 0.5-35 mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5 mg,0.1-2.5 mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0.01-0.5 mg/kg,0.015-0.5 mg/kg, 0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg,0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg,0.0015-0.05 mg/kg, or 0.0015-0.04 mg/kg. In some embodiments, thebrivaracetam or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof administered is in an extended releaseform, a controlled release form, a prolonged release form, a sustainedrelease form, a delayed release form, or a slow release form. In someembodiments, the brivaracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof administered isadministered once or twice daily.

In accordance with another aspect of the present invention, there isprovided a method for treating cognitive impairment or improvingcognitive function, delaying or slowing the progression of cognitiveimpairment, or reducing the rate of decline of cognitive function, in asubject suffering from cognitive impairment associated with a centralnervous system (CNS) disorder, or at risk thereof, the method comprisingthe step of administering to said subject a therapeutically effectiveamount of seletracetam or a pharmaceutically acceptable salt thereof. Insome embodiments of this aspect of the invention, the methods improve ortreat cognitive function in said subject. In some embodiments of thisaspect of the invention, the methods delay or slow the progression ofcognitive impairment in said subject. In some embodiments of this aspectof the invention, the methods reduce the rate of decline of cognitivefunction in said subject. In some embodiments of this aspect of theinvention, the methods prevent or slow the progression of the cognitiveimpairment associated with said CNS disorder in said subject. In otherembodiments of this aspect of invention, the methods alleviate,ameliorate, or slow the progression, of one or more symptoms associatedwith the cognitive impairment aspects of said CNS disorder in saidsubject.

In some embodiments of this aspect of the invention, the cognitiveimpairment is associated with age-related cognitive impairment, such asMild Cognitive Impairment (MCI), Age-Associated Memory Impairment(AAMI), Age Related Cognitive Decline (ARCD). In one embodiment of thisaspect of the invention, the MCI is amnestic MCI. In some embodiments ofthis aspect of the invention, the cognitive impairment is associatedwith dementia, Alzheimer's Disease (AD), prodromal AD, post traumaticstress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophiclateral sclerosis, cancer-therapy-related cognitive impairment, mentalretardation, Parkinson's disease, autism, compulsive behavior, orsubstance addiction. In one embodiment, the subject that suffers suchcognitive impairment is a human patient.

In certain embodiments of this aspect of the invention, the seletracetamor a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of at least 0.1 mg, 0.5mg, 0.75 mg, 1.0 mg, 1.5 mg, or 2.0 mg; but no more than a daily dose of2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg. In otherembodiments, the seletracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015mg/kg, 0.02 mg/kg, or 0.03 mg/kg; but no more than a daily dose of 0.5mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05mg/kg, or 0.04 mg/kg. In other embodiments, the seletracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of about 0.1-350 mg,0.7-350 mg, 3-300 mg, 3-150 mg, 3-110 mg, or 7-70 mg; or 0.0015-5 mg/kg,0.01-5 mg/kg, 0.05-4.0 mg/kg, 0.05-2 mg/kg, 0.05-1.5 mg/kg, or 0.1-1mg/kg.

In certain embodiments of this aspect of the invention, the seletracetamor a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose according to one of thedaily dose ranges indicated as “+” listed in Tables 7-10. For example,the seletracetam or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof may be administered at a dailydose of 0.1-35 mg, 0.5-35 mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35mg, 0.1-30 mg, 0.1-25 mg, 0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5 mg,0.1-2.5 mg, 0.0015-0.5 mg/kg, 0.0075-0.5 mg/kg, 0.01-0.5 mg/kg,0.015-0.5 mg/kg, 0.02-0.5 mg/kg, 0.03-0.5 mg/kg, 0.0015-0.4 mg/kg,0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg, 0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg,0.0015-0.05 mg/kg, or 0.0015-0.04 mg/kg. In some embodiments, theseletracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof administered is in an extended releaseform, a controlled release form, a prolonged release form, a sustainedrelease form, a delayed release form, or a slow release form. In someembodiments, the seletracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof administered isadministered once or twice daily.

In certain embodiments of the various aspect of the invention, the SV2Ainhibitor (e.g., levetiracetam, brivaracetam, or seletracetam) or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered in an extended release form, acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form. In someembodiments, the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in an extended releaseform (or a controlled release form, a prolonged release form, asustained release form, a delayed release form, or a slow release form)is administered together with valproate or an analog, derivative,pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In some embodiments, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form) and valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof are administered separately. In some ofthe above embodiments where the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is inan extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form), valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is alsoin an extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form). In some of the above embodiments where the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form), valproate or ananalog, derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is not in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments of the invention, valproate or an analog, derivative,pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments, valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof in anextended release form (or a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form) is administered together with the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof. In some embodiments, valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form) and the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof are administered separately.

In some of the above embodiments where valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form), the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is also in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In some of theabove embodiments where valproate or an analog, derivative,pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form), the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is not in an extended release form (or a controlledrelease form, a prolonged release form, a sustained release form, adelayed release form, or a slow release form).

In some of the above embodiments where the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form), the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof are administered once daily. In some of the aboveembodiments where valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is inan extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form), the valproate or the analog, derivative orpharmaceutically acceptable salt thereof are administered once daily.

In some of the above embodiments, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is levetiracetam, brivaracetam, or seletracetam. In someof the above embodiments, levetiracetam, brivaracetam, or seletracetamor a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form). In some of the above embodimentswhere levetiracetam, brivaracetam, or seletracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is inan extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form), the levetiracetam, brivaracetam, or seletracetam orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered daily.

In some of the above embodiments, the effect of the treatment, theprogression of cognitive impairment, or the rate of decline of cognitivefunction is measured by detecting the difference between the levels ofreelin in the subject prior to and after the administration step.

In some of the above embodiments, the effect of the treatment, theprogression of cognitive impairment, or the rate of decline of cognitivefunction is measured by detecting the difference between the levels ofsomatostatin in the subject prior to and after the administration step.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts increased mRNA expression of the gene encoding SV2A inthe dentate gyms of the hippocampus of aged-impaired rats (AI) ascompared to young rats (Y) and aged-unimpaired rats (AU). NormalizedAffymetrix GeneChip probe set signal values (Y-axis), as a measure ofmRNA expression, are plotted against learning indices of different rats,as a measure of cognitive impairment.

FIG. 2 depicts the effects of administering levetiracetam on the spatialmemory retention of six aged-impaired rats (AI) in a Morris Water Maze(MWM) test. Three treatment conditions were employed: vehicle control,levetiracetam (5 mg/kg/day) and levetiracetam (10 mg/kg/day). The AIrats were trained for two consecutive days, with a one-time treatmentprior to the training trials per day. 24 hours later, the AI rats weretested. The time the AI rats, 24 hours after treatment with thedifferent conditions and two days of training, spent swimming in thetarget quadrant or the target annulus in a memory retention trial isused as a measure of spatial memory retention. The target quadrantrefers to the quadrant of the maze (which is a circular pool) where theescape platform is placed during the training trials. The target annulusrefers to the exact location of the escape platform during the trainingtrials.

FIG. 3 depicts the effects of administering levetiracetam on the spatialmemory retention of ten aged-impaired rats (AI) in an eight-arm RadialArm Maze (RAM) test. Six treatment conditions were employed: vehiclecontrol, levetiracetam (1.25 mg/kg), levetiracetam (2.5 mg/kg),levetiracetam (5 mg/kg), levetiracetam (10 mg/kg) and levetiracetam (20mg/kg). In the RAM task used, there was a one-hour delay betweenpresentation of a subset of arms (5 arms available and 3 arms blocked)and completion of the eight-arm win-shift task (eight arms available).Rats were pre-treated 30-40 minutes before daily trials with a one-timedrug/control treatment. The number of errors made by the rats after thedelay was used as a measure of spatial memory retention. Errors weredefined as instances when rats entered an arm from which food hadalready been retrieved in the pre-delay component of the trial or whenrats re-visited an arm in the post-delay session that had already beenvisited. Paired t-tests were used to compare the number of errorsbetween different doses of levetiracetam and vehicle control.

FIG. 4 depicts the effects of administering levetiracetam or valproateseparately on the spatial memory retention of ten aged-impaired rats(AI) in an eight-arm Radial Arm Maze (RAM) test.

FIG. 5 depicts the effects of administering levetiracetam or valproatein combination on the spatial memory retention of ten aged-impaired rats(AI) in an eight-arm Radial Arm Maze (RAM) test.

FIG. 6 shows an isobologram plotting levetiracetam dose againstvalproate dose. The diagonal straight line is the line of additivity,anchored on each axis by the lowest effective doses of valproate andlevetiracetam when assessed individually.

FIG. 7 depicts the experimental design of the human trials forlevetiracetam treatment.

FIG. 8A depicts the average activity in the left CA3 of aMCI subjectswith placebo treatment and age-matched control subjects with placebotreatment during the presentation of lure stimuli that the subjectcorrectly identified as “similar.”

FIG. 8B depicts the average activity in the left CA3 of aMCI subjectswith placebo treatment or levetiracetam treatment (125 mg twice a dayfor two weeks) during the presentation of lure stimuli that the subjectcorrectly identified as “similar.”

FIG. 8C is a table of the data represented in FIGS. 8A and 8B.

FIG. 9A depicts the average activity in the left entorhinal cortex ofage-matched control subjects with placebo treatment and aMCI subjectswith placebo treatment during the presentation of lure stimuli that thesubject correctly identified as “similar.”

FIG. 9B depicts the average activity in the left entorhinal cortex ofthe same aMCI subjects with placebo treatment or levetiracetam treatment(125 mg twice a day for two weeks) during the presentation of lurestimuli that the subject correctly identified as “similar.”

FIG. 9C is a table of the data represented in FIGS. 9A and 9B.

FIG. 10A depicts an example of the sequence of images shown to subjectsin the explicit 3-alternative forced choice task described in Example 3.

FIG. 10B shows sample pairs of similar (“lure”) images.

FIG. 11 shows the difference between the aMCI (placebo) subjects andage-matched control (placebo) subjects in their performance of theexplicit 3-alternative forced choice task described in Example 3. Eachbar represents the proportion of the subject responses (old, similar, ornew) when presented with a lure image.

FIG. 12 shows the difference between the same aMCI subjects with placebotreatment or with levetiracetam treatment (125 mg twice a day for twoweeks) in their performance of the explicit 3-alternative forced choicetask described in Example 2. Each bar represents the proportion of thesubjects responses (old, similar, or new) when presented with a lureimage.

FIG. 13 is a table of the data represented in FIGS. 11 and 12.

FIG. 14A shows the difference between the age-matched control (placebo)subjects and the aMCI subjects treated with placebo or withlevetiracetam (125 mg twice a day for two weeks) in their performance ofthe Bushke Selective reminding Test—Delayed Recall.

FIG. 14B is a table of the data represented in FIG. 14A.

FIG. 15A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Benton VisualRetention Test.

FIG. 15B is a table of the data represented in FIG. 15A.

FIG. 16A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Verbal PairedAssociates Test—Recognition.

FIG. 16B is a table of the data represented in FIG. 16A.

FIG. 17A shows the difference between the control (placebo) subjects andthe aMCI subjects treated with placebo or with levetiracetam (125 mgtwice a day for two weeks) in their performance of the Verbal PairedAssociates Test—Delayed Recall.

FIG. 17B is a table of the data represented in FIG. 17A.

FIG. 18A is a table showing the subject selection process for the humanlevetiracetam trial described in Example 2.

FIG. 18B is a table showing the characteristics of the subjects selectedfor the human levetiracetam trial described in Example 2.

FIG. 19 depicts the effects of administering brivaracetam on the memoryperformance of nine aged-impaired rats in an eight-arm Radial Arm Mazetask. Doses of brivaracetam administered to the AI rats include 0.0625mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg.Means and SEMs for the number of errors are shown as the y-axis.

FIG. 20 depicts the effects of administering seletracetam on the memoryperformance of nine aged-impaired rats in an eight-arm Radial Arm Mazetest. Doses of seletracetam administered to the AI rats include include0.0625 mg/kg, 0.125 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4mg/kg. Means and SEMs for the number of errors are shown as the y-axis.

FIG. 21A and FIG. 21B depict the performance of aged-impaired rats(n=3/group) treated with brivaracetam at a dose of 2 mg/kg/day after 14days in the water maze task. Rats treated with brivaracetam at 2mg/kg/day (t(2)=10.000, p=0.010) but not vehicle (t(2)=1.964, p=0.188)showed a significant spatial bias for the target quadrant compared tothe other controls quadrants. Brivaracetam-treated rats (2 mg/kg/day)also spent significantly more time in the target quadrant than thevehicle-treated rats, t(4)=3.881, p=0.018. Brivaracetam-treated rats (2mg/kg/day) spent significantly more time in the target annulus (areasurrounding the location of the escape platform) than thevehicle-treated rats, t(4)=3.109, p=0.036.

FIG. 22A and FIG. 22B depict the effects of levetiracetam on fMRIactivities in Dentate Gyrus/CA3 region of aMCI patients at a dose of62.5 mg BID and 250 mg BID.

FIG. 23A and FIG. 23B show the difference between the aMCI (placebo)subjects and age-matched control (placebo) subjects in their performanceof the explicit 3-alternative forced choice task described in Example 4at a dose of 62.5 mg BID placebo and 250 mg BID placebo. Each barrepresents the proportion of the subject responses (old, similar, ornew) when presented with a lure image.

FIG. 24A and FIG. 24B show the difference between the same aMCI subjectswith placebo treatment or with levetiracetam treatment (62.5 mg BID and250 mg BID) in their performance of the explicit 3-alternative forcedchoice task described in Example 4. Each bar represents the proportionof the subjects responses (old, similar, or new) when presented with alure image.

FIG. 25 shows that administering levetiracetam at a dose of 10 mg/kg/dayand vehicle in osmotic minipumps for four weeks in aged-impaired ratsrestores sematostatin in DG hilus.

FIG. 26 shows that administering levetiracetam at a dose of 10 mg/kg/dayand vehicle in osmotic minipumps for four weeks in aged-impaired ratsrestores reelin in Entorhinal Cortex (EC2).

FIGS. 27A-27C depict the levetiracetam blood plasma levels for the aMCIpatients at a dose of 62.5 mg BID, 125 mg BID and 250 mg BIDlevetiracetam.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature used inconnection with, and techniques of, cell and tissue culture, molecularbiology, cell and cancer biology, neurobiology, neurochemistry,virology, immunology, microbiology, pharmacology, genetics and proteinand nucleic acid chemistry, described herein, are those well known andcommonly used in the art.

The methods and techniques of the present invention are generallyperformed, unless otherwise indicated, according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout thisspecification. See, e.g. “Principles of Neural Science”, McGraw-HillMedical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”,Oxford University Press, Inc. (1995); Lodish et al., “Molecular CellBiology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths etal., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co.,N.Y. (1999); Gilbert et al., “Developmental Biology, 6th ed.”, SinauerAssociates, Inc., Sunderland, Mass. (2000).

Chemistry terms used herein are used according to conventional usage inthe art, as exemplified by “The McGraw-Hill Dictionary of ChemicalTerms”, Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

All of the above, and any other publications, patents and publishedpatent applications referred to in this application are specificallyincorporated by reference herein. In case of conflict, the presentspecification, including its specific definitions, will control.

Throughout this specification, the word “comprise” or variations such as“comprises” or “comprising” will be understood to imply the inclusion ofa stated integer (or components) or group of integers (or components),but not the exclusion of any other integer (or components) or group ofintegers (or components).

The singular forms “a,” “an,” and “the” include the plurals unless thecontext clearly dictates otherwise.

The term “including” is used to mean “including but not limited to”.“Including” and “including but not limited to” are used interchangeably.

The term “agent” is used herein to denote a chemical compound (such asan organic or inorganic compound, a mixture of chemical compounds), abiological macromolecule (such as a nucleic acid, an antibody, includingparts thereof as well as humanized, chimeric and human antibodies andmonoclonal antibodies, a protein or portion thereof, e.g., a peptide, alipid, a carbohydrate), or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Agents include, for example, agents which are knownwith respect to structure, and those which are not known with respect tostructure. The SV2A inhibitory activity of such agents may render themsuitable as “therapeutic agents” in the methods and compositions of thisinvention.

A “patient”, “subject”, or “individual” are used interchangeably andrefer to either a human or a non-human animal. These terms includemammals, such as humans, primates, livestock animals (including bovines,porcines, etc.), companion animals (e.g., canines, felines, etc.) androdents (e.g., mice and rats).

“Cognitive function” or “cognitive status” refers to any higher orderintellectual brain process or brain state, respectively, involved inlearning and/or memory including, but not limited to, attention,information acquisition, information processing, working memory,short-term memory, long-term memory, anterograde memory, retrogradememory, memory retrieval, discrimination learning, decision-making,inhibitory response control, attentional set-shifting, delayedreinforcement learning, reversal learning, the temporal integration ofvoluntary behavior, and expressing an interest in one's surroundings andself-care, speed of processing, reasoning and problem solving and socialcognition.

In humans, cognitive function may be measured, for example and withoutlimitation, by the clinical global impression of change scale(CIBIC-plus scale); the Mini Mental State Exam (MMSE); theNeuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale(CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB);the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke SelectiveReminding Test (Buschke and Fuld, 1974); the Verbal Paired Associatessubtest; the Logical Memory subtest; the Visual Reproduction subtest ofthe Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the BentonVisual Retention Test; or the explicit 3-alternative forced choice task,or MATRICS consensus neuropsychological test battery. See Folstein etal., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger etal., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002and Masur et al., 1994. Also see Buchanan, R. W., Keefe, R. S. E.,Umbricht, D., Green, M. F., Laughren, T., and Marder, S. R. (2011), TheFDA-NIMH-MATRICS guidelines for clinical trial design ofcognitive-enhancing drugs: what do we know 5 years later? Schizophr.Bull. 37, 1209-1217.

In animal model systems, cognitive function may be measured in variousconventional ways known in the art, including using a Morris Water Maze(MWM), Barnes circular maze, elevated radial arm maze, T maze or anyother mazes in which the animals use spatial information. Cognitivefunction can be assessed by reversal learning, extradimensional setshifting, conditional discrimination learning and assessments of rewardexpectancy. Other tests known in the art may also be used to assesscognitive function, such as novel object recognition and odorrecognition tasks.

Cognitive function may also be measured using imaging techniques such asPositron Emission Tomography (PET), functional magnetic resonanceimaging (fMRI), Single Photon Emission Computed Tomography (SPECT), orany other imaging technique that allows one to measure brain function.In animals, cognitive function may also be measured withelectrophysiological techniques.

“Promoting” cognitive function refers to affecting impaired cognitivefunction so that it more closely resembles the function of a normal,unimpaired subject. Cognitive function may be promoted to any detectabledegree, but in humans preferably is promoted sufficiently to allow animpaired subject to carry out daily activities of normal life a level ofproficiency as close as possible to a normal, unimpaired subject or anage-matched normal, unimpaired subject.

In some cases, “promoting” cognitive function in a subject affected byage-related cognitive refers to affecting impaired cognitive function sothat it more closely resembles the function of an aged-matched normal,unimpaired subject, or the function of a young adult subject. Cognitivefunction of that subject may be promoted to any detectable degree, butin humans preferably is promoted sufficiently to allow an impairedsubject to carry out daily activities of normal life at a level ofproficiency as close as possible to a normal, unimpaired subject or ayoung adult subject or an age-matched normal, unimpaired subject.

“Preserving” cognitive function refers to affecting normal or impairedcognitive function such that it does not decline or does not fall belowthat observed in the subject upon first presentation or diagnosis, ordelays such decline.

“Improving” cognitive function includes promoting cognitive functionand/or preserving cognitive function in a subject.

“Cognitive impairment” refers to cognitive function in subjects that isnot as robust as that expected in a normal, unimpaired subject. In somecases, cognitive function is reduced by about 5%, about 10%, about 30%,or more, compared to cognitive function expected in a normal, unimpairedsubject. In some cases, “cognitive impairment” in subjects affected byaged-related cognitive impairment refers to cognitive function insubjects that is not as robust as that expected in an aged-matchednormal, unimpaired subject, or the function of a young adult subject(i.e. subjects with mean scores for a given age in a cognitive test).

“Age-related cognitive impairment” refers to cognitive impairment inaged subjects, wherein their cognitive function is not as robust as thatexpected in an age-matched normal subject or as that expected in youngadult subjects. In some cases, cognitive function is reduced by about5%, about 10%, about 30%, or more, compared to cognitive functionexpected in an age-matched normal subject. In some cases, cognitivefunction is as expected in an age-matched normal subject, but reduced byabout 5%, about 10%, about 30%, about 50% or more, compared to cognitivefunction expected in a young adult subject. Age-related impairedcognitive function may be associated with Mild Cognitive Impairment(MCI) (including amnestic MCI and non-amnestic MCI), Age-AssociatedMemory Impairment (AAMI), and Age-related Cognitive Decline (ARCD).

“Cognitive impairment” associated with AD or related to AD or in ADrefers to cognitive function in subjects that is not as robust as thatexpected in subjects who have not been diagnosed AD using conventionalmethodologies and standards.

“Mild Cognitive Impairment” or “MCI” refers to a condition characterizedby isolated memory impairment unaccompanied other cognitiveabnormalities and relatively normal functional abilities. One set ofcriteria for a clinical characterization of MCI specifies the followingcharacteristics: (1) memory complaint (as reported by patient,informant, or physician), (2) normal activities of daily living (ADLs),(3) normal global cognitive function, (4) abnormal memory for age(defined as scoring more than 1.5 standard deviations below the mean fora given age), and (5) absence of indicators of dementia (as defined byDSM-IV guidelines). Petersen et al., Srch. Neurol. 56: 303-308 (1999);Petersen, “Mild cognitive impairment: Aging to Alzheimer's Disease.”Oxford University Press, N.Y. (2003).

Diagnosis of MCI usually entails an objective assessment of cognitiveimpairment, which can be garnered through the use of well-establishedneuropsychological tests, including the Mini Mental State Examination(MMSE), the Cambridge Neuropsychological Test Automated Battery (CANTAB)and individual tests such as Rey Auditory Verbal Learning Test (AVLT),Logical Memory Subtest of the revised Wechsler Memory Scale (WMS-R) andthe New York University (NYU) Paragraph Recall Test. See Folstein etal., J Psychiatric Res 12: 189-98 (1975); Robbins et al., Dementia 5:266-81 (1994); Kluger et al., J Geriatric Psychiatry Neurol 12:168-79(1999).

“Age-Associate Memory Impairment (AAMI)” refers to a decline in memorydue to aging. A patient may be considered to have AAMI if he or she isat least 50 years old and meets all of the following criteria: a) Thepatient has noticed a decline in memory performance, b) The patientperforms worse on a standard test of memory compared to young adults, c)All other obvious causes of memory decline, except normal aging, havebeen ruled out (in other words, the memory decline cannot be attributedto other causes such as a recent heart attack or head injury,depression, adverse reactions to medication, Alzheimer's disease, etc.).

“Age-Related Cognitive Decline (ARCD)” refers to declines in memory andcognitive abilities that are a normal consequence of aging in humans(e.g., Craik & Salthouse, 1992). This is also true in virtually allmammalian species. Age-Associated Memory Impairment refers to olderpersons with objective memory declines relative to their younger years,but cognitive functioning that is normal relative to their age peers(Crook et al., 1986). Age-Consistent Memory Decline, is a lesspejorative label which emphasizes that these are normal developmentalchanges (Crook, 1993; Larrabee, 1996), are not pathophysiological (Smithet al., 1991), and rarely progress to overt dementia (Youngjohn & Crook,1993). The DSM-IV (1994) has codified the diagnostic classification ofARCD.

Alzheimer's disease (AD) is characterized by memory deficits in itsearly phase. Later symptoms include impaired judgment, disorientation,confusion, behavior changes, trouble speaking, and motor deficits.Histologically, AD is characterized by beta-amyloid plaques and tanglesof protein tau.

Vascular dementia is caused by strokes. Symptoms overlap with those ofAD, but without the focus on memory impairment.

Dementia with Lewy bodies is characterized by abnormal deposits ofalpha-synuclein that form inside neurons in the brain. Cognitiveimpairment may be similar to AD, including impairments in memory andjudgment and behavior changes.

Frontotemporal dementia is characterized by gliosis, neuronal loss,superficial spongiform degeneration in the frontal cortex and/oranterior temporal lobes, and Picks' bodies. Symptoms include changes inpersonality and behavior, including a decline in social skills andlanguage expression/comprehension.

“Post traumatic stress disorder (PTSD)” refers to an anxiety disordercharacterized by an immediate or delayed response to a catastrophicevent, characterized by re-experiencing the trauma, psychic numbing oravoidance of stimuli associated with the trauma, and increased arousal.Re-experiencing phenomena include intrusive memories, flashbacks,nightmares, and psychological or physiological distress in response totrauma reminders. Such responses produce anxiety and can havesignificant impact, both chronic and acute, on a patient's quality oflife and physical and emotional health. PTSD is also associated withimpaired cognitive performance, and older individuals with PTSD havegreater decline in cognitive performance relative to control patients.

“Schizophrenia” refers to a chronic debilitating disorder, characterizedby a spectrum of psychopathology, including positive symptoms such asaberrant or distorted mental representations (e.g., hallucinations,delusions), negative symptoms characterized by diminution of motivationand adaptive goal-directed action (e.g., anhedonia, affectiveflattening, avolition), and cognitive impairment. While abnormalities inthe brain are proposed to underlie the full spectrum of psychopathologyin schizophrenia, currently available antipsychotics are largelyineffective in treating cognitive impairments in patients.

“Bipolar disorder” or “BP” or “manic depressive disorder” or “manicdepressive illness” refers to a chronic psychological/mood disorderwhich can be characterized by significant mood changes including periodsof depression and euphoric manic periods. BP may be diagnosed by askilled physician based on personal and medical history, interviewconsultation and physical examinations. The term “mania” or “manicperiods” or other variants refers to periods where an individualexhibits some or all of the following characteristics: racing thoughts,rapid speech, elevated levels of activity and agitation as well as aninflated sense of self-esteem, euphoria, poor judgment, insomnia,impaired concentration and aggression.

“Amyotrophic lateral sclerosis,” also known as ALS, refers to aprogressive, fatal, neurodegenerative disease characterized by adegeneration of motor neurons, the nerve cells in the central nervoussystem that control voluntary muscle movement. ALS is also characterizedby neuronal degeneration in the entorhinal cortex and hippocampus,memory deficits, and neuronal hyperexcitability in different brain areassuch as the cortex.

“Cancer therapy-related cognitive impairment” refers to cognitiveimpairment that develops in subjects that are treated with cancertherapies such as chemotherapy and radiation. Cytotoxicity and otheradverse side-effects on the brain of cancer therapies result incognitive impairment in such functions as memory, learning andattention.

Parkinson's disease (PD) is a neurological disorder characterized by adecrease of voluntary movements. The afflicted patient has reduction ofmotor activity and slower voluntary movements compared to the normalindividual. The patient has characteristic “mask” face, a tendency tohurry while walking, bent over posture and generalized weakness of themuscles. There is a typical “lead-pipe” rigidity of passive movements.Another important feature of the disease is the tremor of theextremities occurring at rest and decreasing during movements.

“Autism”, as used herein, refers to an autism spectrum disordercharacterized by a neural development disorder leading to impairedsocial interaction and communication by restricted and repetitivebehavior. “Autism Spectrum Disorder” refers to a group of developmentaldisabilities that includes: autism; Asperger syndrome; pervasivedevelopmental disorder not otherwise specified (PDD-NOS or atypicalautism); Rett syndrome; and childhood disintegrative disorder.

Mental retardation is a generalized disorder characterized bysignificantly impaired cognitive function and deficits in adaptivebehaviors. Mental retardation is often defined as an IntelligenceQuotient (IQ) score of less than 70. Inborn causes are among manyunderlying causes for mental retardation. The dysfunction in neuronalcommunication is also considered one of the underlying causes for mentalredardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol.Neurosci. Rep. 2010, 10, 207-214).

In some instances, mental retardation includes, but are not limited to,Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, FragileX syndrome, Klinefelter's syndrome, neurofibromatosis, congenitalhypothyroidism, Williams syndrome, phenylketonuria (PKU),Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermidsyndrome, Mowat-Wilson syndrome, ciliopathy, Lowe syndrome and sideriumtype X-linked mental retardation. Down syndrome is a disorder thatincludes a combination of birth defects, including some degree of mentalretardation, characteristic facial features and, often, heart defects,increased infections, problems with vision and hearing, and other healthproblems. Fragile X syndrome is a prevalent form of inherited mentalretardation, occurring with a frequency of 1 in 4,000 males and 1 in8,000 females. The syndrome is also characterized by developmentaldelay, hyperactivity, attention deficit disorder, and autistic-likebehavior. There is no effective treatment for fragile X syndrome.

Obsessive compulsive disorder (“OCD”) is a mental condition that is mostcommonly characterized by intrusive, repetitive unwanted thoughts(obsessions) resulting in compulsive behaviors and mental acts that anindividual feels driven to perform (compulsion). Current epidemiologicaldata indicates that OCD is the fourth most common mental disorder in theUnited States. Some studies suggest the prevalence of OCD is between oneand three percent, although the prevalence of clinically recognized OCDis much lower, suggesting that many individuals with the disorder maynot be diagnosed. Patients with OCD are often diagnosed by apsychologist, psychiatrist, or psychoanalyst according to the Diagnosticand Statistical Manual of Mental Disorders, 4th edition text revision(DSM-IV-TR) (2000) diagnostic criteria that include characteristics ofobsessions and compulsions.

Substance addiction (e.g., drug addiction, alcohol addiction) is amental disorder. The addiction is not triggered instantaneously uponexposure to substnace of abuse. Rather, it involves multiple, complexneural adaptations that develop with different time courses ranging fromhours to days to months (Kauer J. A. Nat. Rev. Neurosci. 2007, 8,844-858). The path to addiction generally begins with the voluntary useof one or more controlled substances, such as narcotics, barbiturates,methamphetamines, alcohol, nicotine, and any of a variety of other suchcontrolled substances. Over time, with extended use of the controlledsubstance(s), the voluntary ability to abstain from the controlledsubstance(s) is compromised due to the effects of prolonged use on brainfunction, and thus on behavior. As such, substance addiction generallyis characterized by compulsive substance craving, seeking and use thatpersist even in the face of negative consequences. The cravings mayrepresent changes in the underlying neurobiology of the patient whichlikely must be addressed in a meaningful way if recovery is to beobtained. Substance addiction is also characterized in many cases bywithdrawal symptoms, which for some substances are life threatening(e.g., alcohol, barbiturates) and in others can result in substantialmorbidity (which may include nausea, vomiting, fever, dizziness, andprofuse sweating), distress, and decreased ability to obtain recovery.For example, alcoholism, also known as alcohol dependence, is one suchsubstance addiction. Alcoholism is primarily characterized by foursymptoms, which include cravings, loss of control, physical dependenceand tolerance. These symptoms also may characterize addictions to othercontrolled substances. The craving for alcohol, as well as othercontrolled substances, often is as strong as the need for food or water.Thus, an alcoholic may continue to drink despite serious family, healthand/or legal ramifications.

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. Beneficial ordesired clinical results include, but are not limited to, improvingcognitive function, delaying or slowing the progression of cognitiveimpairment, reducing the rate of decline of cognitive function,preventing or slowing the progression of the disease or disorder, oralleviation, amelioration, or slowing the progression, of one or moresymptoms associated of cognitive impairment associated with CNSdisorders, such as age-related cognitive impairment, Mild CognitiveImpairment (MCI), amnestic MCI, dementia, Alzheimer's Disease (AD),prodromal AD, PTSD, schizophrenia or bipolar disorder (in particular,mania), amyotrophic lateral sclerosis (ALS) or cancer therapy-relatedcognitive impairment. Treating age-related cognitive impairment furthercomprises slowing the conversion of age-related cognitive impairment(including, but not limited to MCI, ARCD and AAMI) into dementia (e.g.,AD).

“Treating cognitive impairment” refers to taking steps to improvecognitive function in a subject with cognitive impairment so that thesubject's performance in one or more cognitive tests is improved to anydetectable degree, or is prevented from further decline. Preferably,that subject's cognitive function, after treatment of cognitiveimpairment, more closely resembles the function of a normal, unimpairedsubject. Treatment of cognitive impairment in humans may improvecognitive function to any detectable degree, but is preferably improvedsufficiently to allow the impaired subject to carry out daily activitiesof normal life at the same level of proficiency as a normal, unimpairedsubject. In some cases, “treating cognitive impairment” refers to takingsteps to improve cognitive function in a subject with cognitiveimpairment so that the subject's performance in one or more cognitivetests is improved to any detectable degree, or is prevented from furtherdecline. Preferably, that subject's cognitive function, after treatmentof cognitive impairment, more closely resembles the function of anormal, unimpaired subject. In some cases, “treating cognitiveimpairment” in a subject affecting by age-related cognitive impairmentrefers to takings steps to improve cognitive function in the subject sothat the subject's cognitive function, after treatment of cognitiveimpairment, more closely resembles the function of an age-matchednormal, unimpaired subject, or the function of a young adult subject. Insome cases, “treating cognitive impairment” in a subject refers totaking steps to delay or slow the progression of cognitive impairment ina subject with cognitive impairment. In some cases, “treating cognitiveimpairment” in a subject refers to taking steps to reduce the rate ofdecline of cognitive function in a subject with cognitive impairment.

“Administering” or “administration of” a substance, a compound or anagent to a subject can be carried out using one of a variety of methodsknown to those skilled in the art. For example, a compound or an agentcan be administered, intravenously, arterially, intradermally,intramuscularly, intraperitonealy, intravenously, subcutaneously,ocularly, sublingually, orally (by ingestion), intranasally (byinhalation), intraspinally, intracerebrally, and transdermally (byabsorption, e.g., through a skin duct). A compound or agent can alsoappropriately be introduced by rechargeable or biodegradable polymericdevices or other devices, e.g., patches and pumps, or formulations,which provide for the extended, slow or controlled release of thecompound or agent. Administering can also be performed, for example,once, a plurality of times, and/or over one or more extended periods. Insome aspects, the administration includes both direct administration,including self-administration, and indirect administration, includingthe act of prescribing a drug. For example, as used herein, a physicianwho instructs a patient to self-administer a drug, or to have the drugadministered by another and/or who provides a patient with aprescription for a drug is administering the drug to the patient.

Appropriate methods of administering a substance, a compound or an agentto a subject will also depend, for example, on the age of the subject,whether the subject is active or inactive at the time of administering,whether the subject is cognitively impaired at the time ofadministering, the extent of the impairment, and the chemical andbiological properties of the compound or agent (e.g. solubility,digestibility, bioavailability, stability and toxicity). In someembodiments, a compound or an agent is administered orally, e.g., to asubject by ingestion, or intravenously, e.g., to a subject by injection.In some embodiments, the orally administered compound or agent is in anextended release or slow release formulation, or administered using adevice for such slow or extended release.

As used herein, administration of an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof “incombination” or “together” includes simultaneous administration and/oradministration at different times, such as sequential administration. Italso includes administration in a single formulation or in separateformulation packaged together. For example, the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be formulated/administered in an extended releaseform, which may be administered together or separately with valproate oran analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof, wherein valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof may or may not be in an extended releaseform itself. In some embodiments, valproate or an analog, derivative,pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be formulated/administered in an extended releaseform, which may be administered together or separately with an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof, wherein the SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may or may not be in an extended release form itself.

The term “simultaneous administration,” as used herein, means that theSV2A inhibitor or its pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug and valproate or its analog, derivativeor pharmaceutically acceptable salt, are administered with a timeseparation of no more than about 15 minutes, and in some embodiments nomore than about 10 minutes. When the drugs are administeredsimultaneously, the SV2A inhibitor or its pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug and valproate or itsanalog, derivative or pharmaceutically acceptable salt, may be containedin the same dosage (e.g., a unit dosage form comprising both the SV2Ainhibitor and the valproate) or in discrete dosages (e.g., the SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug, is contained in one dosage form and the valproateor its analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug, is contained in another dosage form).

The term “sequential administration” as used herein means that the SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug are valproate or its analog, derivative orpharmaceutically acceptable salt, are administered with a timeseparation of more than about 15 minutes, and in some embodiments morethan about one hour, or up to 12 hours. Either the SV2A inhibitor thevalproate may be administered first. For sequential administration, heSV2A inhibitor its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug, and valproate or its analog, derivative orpharmaceutically acceptable salt, may be contained in discrete dosageforms, optionally contained in the same container or package.

A “therapeutically effective amount” of a drug or agent is an amount ofa drug or an agent that, when administered to a subject will have theintended therapeutic effect, e.g. improving cognitive function, ordelaying or slowing the progression of cognitive impairment, or reducingthe rate of decline of cognitive function in a subject, e.g., a patienthaving cognitive impairment associated with a CNS disorder with. Thefull therapeutic effect does not necessarily occur by administration ofone dose, and may occur only after administration of a series of doses.Thus, a therapeutically effective amount may be administered in one ormore administrations. The precise effective amount needed for a subjectwill depend upon, for example, the subject's size, health and age, thenature and extent of the cognitive impairment, and the therapeutics orcombination of therapeutics selected for administration, and the mode ofadministration. The skilled worker can readily determine the effectiveamount for a given situation by routine experimentation.

“Subtherapeutic amount” refers to an amount administered of an agent orcompound of the invention that is less than the therapeutic amount, thatis, less than the amount normally used when said agent or compound isadministered alone (i.e., individually and in the absence of othertherapeutic agents or compounds) to treat disorders involving cognitivedysfunction.

“Analog” is used herein to refer to a compound which functionallyresembles another chemical entity, but does not share the identicalchemical structure. For example, an analog is sufficiently similar to abase or parent compound such that it can substitute for the basecompound in therapeutic applications, despite minor structuraldifferences.

“Derivative” is used herein to refer to the chemical modification of acompound. Chemical modifications of a compound can include, for example,replacement of hydrogen by an alkyl, acyl, or amino group. Many othermodifications are also possible.

The term “prodrug” is art-recognized and is intended to encompasscompounds or agents which, under physiological conditions, are convertedinto an SV2A inhibitor valproate. A common method for making a prodrugis to select moieties which are hydrolyzed or metabolized underphysiological conditions to provide the desired compound or agent. Inother embodiments, the prodrug is converted by an enzymatic activity ofthe host animal to an inhibitor of SV2A or valproate.

“Pharmaceutically acceptable salts” is used herein to refer to an agentor a compound according to the invention that is a therapeuticallyactive, non-toxic base and acid salt form of the compounds. The acidaddition salt form of a compound that occurs in its free form as a basecan be obtained by treating said free base form with an appropriate acidsuch as an inorganic acid, for example, a hydrohalic such ashydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like;or an organic acid, such as, for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic, pamoic and thelike. See, e.g., WO 01/062726.

Description of Methods of the Invention

The methods of this invention comprise administration of an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof. The methods of this invention furthercomprise administration of an SV2A inhibitor or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug thereof incombination with administration of valproate or a pharmaceuticallyacceptable salt thereof. The agents or compounds of the SV2A inhibitorthe valproate and their pharmaceutically acceptable salts also includehydrates, solvates, polymorphs, and prodrugs of those agents, compounds,and salts.

Methods of Assessing Cognitive Impairment

Animal models serve as an important resource for developing andevaluating treatments for cognitive impairment associated with CNSdisorders. Features that characterize cognitive impairment in animalmodels typically extend to cognitive impairment in humans. Efficacy insuch animal models is, thus, expected to be predictive of efficacy inhumans. The extent of cognitive impairment in an animal model for a CNSdisorder, and the efficacy of a method of treatment for said CNSdisorder may be tested and confirmed with the use of a variety ofcognitive tests.

A Radial Arm Maze (RAM) behavioral task is one example of a cognitivetest, specifically testing spacial memory (Chappell et al.Neuropharmacology 37: 481-487, 1998). The RAM apparatus consists of,e.g., eight equidistantly spaced arms. A maze arm projects from eachfacet of a center platform. A food well is located at the distal end ofeach arm. Food is used as a reward. Blocks can be positioned to prevententry to any arm. Numerous extra maze cues surrounding the apparatus mayalso be provided. After habituation and training phases, spatial memoryof the subjects may be tested in the RAM under control or testcompound-treated conditions. As a part of the test, subjects arepretreated before trials with a vehicle control or one of a range ofdosages of the test compound. At the beginning of each trial, a subsetof the arms of the eight-arm maze is blocked. Subjects are allowed toobtain food on the unblocked arms to which access is permitted duringthis initial “information phase” of the trial. Subjects are then removedfrom the maze for a delay period, e.g., a 60 second delay, a 15 minutedelay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hourdelay, or longer) between the information phase and the subsequent“retention test,” during which the barriers on the maze are removed,thus allowing access to all eight arms. After the delay period, subjectsare placed back onto the center platform (with the barriers to thepreviously blocked arms removed) and allowed to obtain the remainingfood rewards during this retention test phase of the trial. The identityand configuration of the blocked arms vary across trials. The number of“errors” the subjects make during the retention test phase is tracked.An error occurs in the trial if the subjects entered an arm from whichfood had already been retrieved in the pre-delay component of the trial,or if it re-visits an arm in the post-delay session that had alreadybeen visited. A fewer number of errors would indicate better spatialmemory. The number of errors made by the test subject, under varioustest compound treatment regimes, can then be compared for efficacy ofthe test compound in treating cognitive impairment associated with CNSdisorders.

Another cognitive test that may be used to assess the effects of a testcompound on the cognitive impairment of a CNS disorder model animal isthe Morris water maze. A water maze is a pool surrounded with a novelset of patterns relative to the maze. The training protocol for thewater maze may be based on a modified water maze task that has beenshown to be hippocampal-dependent (de Hoz et al., Eur. J. Neurosci.,22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). Thesubject is trained to locate a submerged escape platform hiddenunderneath the surface of the pool. During the training trial, a subjectis released in the maze (pool) from random starting positions around theperimeter of the pool. The starting position varies from trial to trial.If the subject does not locate the escape platform within a set time,the experimenter guides and places the subject on the platform to“teach” the location of the platform. After a delay period following thelast training trial, a retention test in the absence of the escapeplatform is given to assess spatial memory. The subject's level ofpreference for the location of the (now absent) escape platform, asmeasured by, e.g., the time spent in that location or the number ofcrossings of that location made by the mouse, indicates better spatialmemory, i.e., treatment of cognitive impairment. The preference for thelocation of the escape platform under different treatment conditions,can then be compared for efficacy of the test compound in treatingcognitive impairment associated with CNS disorders.

There are various tests known in the art for assessing cognitivefunction in humans, for example and without limitation, the clinicalglobal impression of change scale (CIBIC-plus scale); the Mini MentalState Exam (MMSE); the Neuropsychiatric Inventory (NPI); the ClinicalDementia Rating Scale (CDR); the Cambridge Neuropsychological TestAutomated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric(SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974);the Verbal Paired Associates subtest; the Logical Memory subtest; theVisual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R)(Wechsler, 1997); the Benton Visual Retention Test, or MATRICS consensusneuropsychological test battery which includes tests of working memory,speed of processing, attention, verbal learning, visual learning,reasoning and problem solving and social cognition. See Folstein et al.,J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger etal., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002and Masur et al., 1994, or MATRICS consensus neuropsychological testbattery which includes tests of working memory, speed of processing,attention, verbal learning, visual learning, reasoning and problemsolving and social cognition. Another example of a cognitive test inhumans is the explicit 3-alternative forced choice task. In this test,subjects are presented with color photographs of common objectsconsisting of a mix of three types of image pairs: similar pairs,identical pairs and unrelated foils. The second of the pair of similarobjects is referred to as the “lure”. These image pairs are fullyrandomized and presented individually as a series of images. Subjectsare instructed to make a judgment as to whether the objects seen arenew, old or similar. A “similar” response to the presentation of a lurestimulus indicates successful memory retrieval by the subject. Bycontrast, calling the lure stimulus “old” or “new” indicates thatcorrect memory retrieval did not occur.

In addition to assessing cognitive performance, the progression ofage-related cognitive impairment and dementia, as well as the conversionof age-related cognitive impairment into dementia, may be monitored byassessing surrogate changes in the brain of the subject. Surrogatechanges include, without limitation, changes in regional brain volumes,perforant path degradation, and changes seen in brain function throughresting state fMRI (R-fMRI) and fluorodeoxyglucose positron emissiontomography (FDG-PET). Examples of regional brain volumes useful inmonitoring the progression of age-related cognitive impairment anddementia include reduction of hippocampal volume and reduction in volumeor thickness of entorhinal cortex. These volumes may be measured in asubject by, for example, MRI. Aisen et al., Alzheimer's & Dementia6:239-246 (2010). Perforant path degradation has been shown to be linkedto age, as well as reduced cognitive function. For example, older adultswith more perforant path degradation tend to perform worse inhippocampus-dependent memory tests. Perforant path degradation may bemonitored in subjects through ultrahigh-resolution diffusion tensorimaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting-statefMRI (R-fMRI) involves imaging the brain during rest, and recordinglarge-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in thefMRI signal that are temporally correlated across functionally relatedareas. Seed-based functional connectivity, independent componentanalyses, and/or frequency-domain analyses of the signals are used toreveal functional connectivity between brain areas, particularly thoseareas whose connectivity increase or decrease with age, as well as theextent of cognitive impairment and/or dementia. FDG-PET uses the uptakeof FDG as a measure of regional metabolic activity in the brain. Declineof FDG uptake in regions such as the posterior cingulated cortex,temporoparietal cortex, and prefrontal association cortex has been shownto relate to the extent of cognitive decline and dementia. Aisen et al.,Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., Neurolmage17:302-316 (2002).

Age-Related Cognitive Impairment

This invention provides methods and compositions for treatingage-related cognitive impairment or the risk thereof using an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof, alone or in combination with valproate oran analog, derivative or pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof. In certain embodiments,treatment comprises improving cognitive function in patients withage-related cognitive impairment. In certain embodiments, treatmentcomprises slowing or delaying the progression of age-related cognitiveimpairment. In certain embodiments, treatment comprises reducing therate of decline of cognitive function associated with age-relatedcognitive impairment. In certain embodiments, treatment comprisespreventing or slowing the progression, of age-related cognitiveimpairment. In certain embodiments, treatment comprises alleviation,amelioration or slowing the progression, of one or more symptomsassociated with age-related cognitive impairment. In certainembodiments, treatment of age-related cognitive impairment comprisesslowing the conversion of age-related cognitive impairment (including,but not limited to MCI, ARCD and AAMI) into dementia (e.g., AD). Themethods and compositions may be used for human patients in clinicalapplications in the treating age-related cognitive impairment inconditions such as MCI, ARCD and AAMI or for the risk thereof. The doseof the composition and dosage interval for the method is, as describedherein, one that is safe and efficacious in those applications.

In some embodiments, a subject to be treated by the methods andcompositions of this invention exhibits age-related cognitive impairmentor is at risk of such impairment. In some embodiments, the age-relatedcognitive impairment includes, without limitation, Age-Associated MemoryImpairment (AAMI), Mild Cognitive Impairment (MCI) and Age-relatedCognitive Decline (ARCD).

Animal models serve as an important resource for developing andevaluating treatments for such age-related cognitive impairments.Features that characterize age-related cognitive impairment in animalmodels typically extend to age-related cognitive impairment in humans.Efficacy in such animal models is, thus, expected to be predictive ofefficacy in humans.

Various animal models of age-related cognitive impairment are known inthe art. For example, extensive behavioral characterization hasidentified a naturally occurring form of cognitive impairment in anoutbred strain of aged Long-Evans rats (Charles River Laboratories;Gallagher et al., Behav. Neurosci. 107:618-626, (1993)). In a behavioralassessment with the Morris Water Maze (MWM), rats learn and remember thelocation of an escape platform guided by a configuration of spatial cuessurrounding the maze. The cognitive basis of performance is tested inprobe trials using measures of the animal's spatial bias in searchingfor the location of the escape platform. Aged rats in the studypopulation have no difficulty swimming to a visible platform, but anage-dependent impairment is detected when the platform is camouflaged,requiring the use of spatial information. Performance for individualaged rats in the outbred Long-Evans strain varies greatly. For example,a proportion of those rats perform on a par with young adults. However,approximately 40-50% fall outside the range of young performance. Thisvariability among aged rats reflects reliable individual differences.Thus, within the aged population some animals are cognitively impairedand designated aged-impaired (AI) and other animals are not impaired andare designated aged-unimpaired (AU). See, e.g., Colombo et al., Proc.Natl. Acad. Sci. 94: 14195-14199, (1997); Gallagher and Burwell,Neurobiol. Aging 10: 691-708, (1989); Gallagher et al. Behav. Neurosci.107:618-626, (1993); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996);Nicolle et al., J. Neurosci. 19: 9604-9610, (1999); International PatentPublication WO2007/019312 and International Patent Publication WO2004/048551. Such an animal model of age-related cognitive impairmentmay be used to assay the effectiveness of the methods and compositionsthis invention in treating age-related cognitive impairment.

The efficacy of the methods and compositions of this invention intreating age-related cognitive impairment may be assessed using avariety of cognitive tests, including the Morris water maze and theradial arm maze, as discussed above.

Dementia

This invention also provides methods and compositions for treatingdementia using an SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof, alone or in combinationwith valproate or an analog, derivative or pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof. In certainembodiments, treatment comprises improving cognitive function inpatients with dementia. In certain embodiments, treatment comprisesslowing or delaying the progression of dementia. In certain embodiments,treatment comprises reducing the rate of decline of cognitive functionassociated with dementia. In certain embodiments, treatment comprisespreventing or slowing the progression, of dementia. In certainembodiments, treatment comprises alleviation, amelioration, or slowingthe progression of one or more symptoms associated with dementia. Incertain embodiments, the symptom to be treated is cognitive impairment.In certain embodiments, the dementia is Alzheimer's disease (AD),vascular dementia, dementia with Lewy bodies, or frontotemporaldementia. The methods and compositions may be used for human patients inclinical applications in treating dementia. The dose of the compositionand dosage interval for the method is, as described herein, one that issafe and efficacious in those applications.

Animal models serve as an important resource for developing andevaluating treatments for dementia. Features that characterize dementiain animal models typically extend to dementia in humans. Thus, efficacyin such animal models is expected to be predictive of efficacy inhumans. Various animal models of dementia are known in the art, such asthe PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg, and APP+PS1 transgenicmice. Sankaranarayanan, Curr. Top. Medicinal Chem. 6: 609-627, 2006;Kobayashi et al. Genes Brain Behav. 4: 173-196. 2005; Ashe and Zahns,Neuron. 66: 631-45, 2010. Such animal models of dementia may be used toassay the effectiveness of the methods and compositions of thisinvention of the invention in treating dementia.

The efficacy of the methods and compositions of this invention intreating dementia, or cognitive impairment associated with dementia, maybe assessed in animals models of dementia, as well as human subjectswith dementia, using a variety of cognitive tests known in the art, asdiscussed above.

Post Traumatic Stress Disorder

This invention also provides methods and compositions for treating posttraumatic stress disorder (PTSD) using an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof, alone or in combination with valproate or an analog,derivative or pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. In certain embodiments, treatmentcomprises improving cognitive function in patients with PTSD. In certainembodiments, treatment comprises slowing or delaying the progression ofPTSD. In certain embodiments, treatment comprises reducing the rate ofdecline of cognitive function associated with PTSD. In certainembodiments, treatment comprises preventing or slowing the progression,of PTSD. In certain embodiments, treatment comprises alleviation,amelioration, or slowing the progression of one or more symptomsassociated with PTSD. In certain embodiments, the symptom to be treatedis cognitive impairment. The methods and compositions may be used forhuman patients in clinical applications in treating PTSD. The dose ofthe composition and dosage interval for the method is, as describedherein, one that is safe and efficacious in those applications.

Patients with PTSD (and, to a lesser degree trauma-exposed patientswithout PTSD) have smaller hippocampal volumes (Woon et al., Prog.Neuro-Psychopharm. & Biological Psych. 34, 1181-1188; Wang et al., Arch.Gen. Psychiatry 67:296-303, 2010). PTSD is also associated with impairedcognitive performance. Older individuals with PTSD have greater declinesin cognitive performance relative to control patients (Yehuda et al.,Bio. Psych. 60: 714-721, 2006) and have a greater likelihood ofdeveloping dementia (Yaffe et al., Arch. Gen. Psych. 678: 608-613,2010).

Animal models serve as an important resource for developing andevaluating treatments for PTSD. Features that characterize PTSD inanimal models typically extend to PTSD in humans. Thus, efficacy in suchanimal models is expected to be predictive of efficacy in humans.Various animal models of PTSD are known in the art.

One rat model of PTSD is Time-dependent sensitization (TDS). TDSinvolves exposure of the animal to a severely stressful event followedby a situational reminder of the prior stress. The following is anexample of TDS. Rats are placed in a restrainer, then placed in a swimtank and made to swim for a period of time, e.g., 20 min. Followingthis, each rat is then immediately exposed to a gaseous anesthetic untilloss of consciousness, and finally dried. The animals are leftundisturbed for a number of days, e.g., one week. The rats are thenexposed to a “restress” session consisting of an initial stressor, e.g.,a swimming session in the swim tank (Liberzon et al.,Psychoneuroendocrinology 22: 443-453, 1997; Harvery et al.,Psychopharmacology 175:494-502, 2004). TDS results in an enhancement ofthe acoustic startle response (ASR) in the rat, which is comparable tothe exaggerated acoustic startle that is a prominent symptom of PTSD(Khan and Liberzon, Psychopharmacology 172: 225-229, 2004). Such animalmodels of PTSD may be used to assay the effectiveness of the methods andcompositions of this invention of the invention in treating PTSD.

The efficacy of the methods and compositions of this invention intreating PTSD, or cognitive impairment associated with PTSD, may also beassessed in animals models of PTSD, as well as human subjects with PTSD,using a variety of cognitive tests known in the art, as discussed above.

Schizophrenia

This invention provides methods and compositions for treatingschizophrenia or bipolar disorder (in particular, mania) using an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof, alone or in combination with valproate oran analog, derivative or pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof. In certain embodiments,treatment comprises improving cognitive function in patients withschizophrenia. In certain embodiments, treatment comprises slowing ordelaying the progression of schizophrenia. In certain embodiments,treatment comprises reducing the rate of decline of cognitive functionassociated with schizophrenia. In certain embodiments, treatmentcomprises preventing or slowing the progression of schizophrenia orbipolar disorder (in particular, mania). Schizophrenia is characterizedby a wide spectrum of psychopathology, including positive symptoms suchas aberrant or distorted mental representations (e.g., hallucinations,delusions), negative symptoms characterized by diminution of motivationand adaptive goal-directed action (e.g., anhedonia, affectiveflattening, avolition), and cognitive impairment. In certainembodiments, treatment comprises alleviation, amelioration or slowingthe progression of one or more positive and/or negative symptoms, aswell as cognitive impairment, associated with schizophrenia. Further,there are a number of other psychiatric diseases such as schizotypicaland schizoaffective disorder, other acute- and chronic psychoses andbipolar disorder (in particular, mania), which have an overlappingsymptomatology with schizophrenia. In some embodiments, treatmentcomprises alleviation, amelioration or slowing the progression of one ormore symptoms, as well as cognitive impairment, associated with bipolardisorder (in particular, mania). The methods and compositions may beused for human patients in clinical applications in treatingschizophrenia or bipolar disorder (in particular, mania). The dose ofthe composition and dosage interval for the method is, as describedherein, one that is safe and efficacious in those applications.

Cognitive impairments are associated with schizophrenia. They precedethe onset of psychosis and are present in non-affected relatives. Thecognitive impairments associated with schizophrenia constitute a goodpredictor for functional outcome and are a core feature of the disorder.Cognitive features in schizophrenia reflect dysfunction in frontalcortical and hippocampal circuits. Patients with schizophrenia alsopresent hippocampal pathologies such as reductions in hippocampalvolume, reductions in neuronal size and dysfunctional hyperactivity. Animbalance in excitation and inhibition in these brain regions has alsobeen documented in schizophrenic patients suggesting that drugstargeting inhibitory mechanisms could be therapeutic. See, e.g.,Guidotti et al., Psychopharmacology 180: 191-205, 2005; Zierhut, Psych.Res. Neuroimag. 183:187-194, 2010; Wood et al., NeuroImage 52:62-63,2010; Vinkers et al., Expert Opin. Investig. Drugs 19:1217-1233, 2009;Young et al., Pharmacol. Ther. 122:150-202, 2009.

Animal models serve as an important resource for developing andevaluating treatments for schizophrenia. Features that characterizeschizophrenia in animal models typically extend to schizophrenia inhumans. Thus, efficacy in such animal models is expected to bepredictive of efficacy in humans. Various animal models of schizophreniaare known in the art.

One animal model of schizophrenia is protracted treatment withmethionine. Methionine-treated mice exhibit deficient expression ofGAD67 in frontal cortex and hippocampus, similar to those reported inthe brain of postmortem schizophrenia patients. They also exhibitprepulse inhibition of startle and social interaction deficits(Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal modelof schizophrenia is methylaoxymethanol acetate (MAM)-treatment in rats.Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) ongestational day 17. MAM-treatment recapitulate a pathodevelopmentalprocess to schizophrenia-like phenotypes in the offspring, includinganatomical changes, behavioral deficits and altered neuronal informationprocessing. More specifically, MAM-treated rats display a decreaseddensity of parvalbumin-positive GABAergic interneurons in portions ofthe prefrontal cortex and hippocampus. In behavioral tests, MAM-treatedrats display reduced latent inhibition. Latent inhibition is abehavioral phenomenon where there is reduced learning about a stimulusto which there has been prior exposure with any consequence. Thistendency to disregard previously benign stimuli, and reduce theformation of association with such stimuli is believed to preventsensory overload. Low latent inhibition is indicative of psychosis.Latent inhibition may be tested in rats in the following manner. Ratsare divided into two groups. One group is pre-exposed to a tone overmultiple trials. The other group has no tone presentation. Both groupsare then exposed to an auditory fear conditioning procedure, in whichthe same tone is presented concurrently with a noxious stimulus, e.g. anelectric shock to the foot. Subsequently, both groups are presented withthe tone, and the rats' change in locomotor activity during tonepresentation is monitored. After the fear conditioning the rats respondto the tone presentation by strongly reducing locomotor activity.However, the group that has been exposed to the tone before theconditioning period displays robust latent inhibition: the suppressionof locomotor activity in response to tone presentation is reduced.MAM-treated rats, by contrast show impaired latent inhibition. That is,exposure to the tone previous to the fear conditioning procedure has nosignificant effect in suppressing the fear conditioning. (see Lodge etal., J. Neurosci., 29:2344-2354, 2009) Such animal models ofschizophrenia may be used to assay the effectiveness of the methods andcompositions of the invention in treating schizophrenia or bipolardisorder (in particular, mania).

MAM-treated rats display a significantly enhanced locomotor response (oraberrant locomotor activity) to low dose D-amphetamine administration.The MAM-treated rats also display a significantly greater number ofspontaneously firing ventral tegmental dopamine (DA) neurons. Theseresults are believed to be a consequence of excessive hippocampalactivity because in MAM-treated rats, the ventral hippocampus (vHipp)inactivation (e.g., by intra-vHipp administration of a sodium channelblocker, tetrodotoxin (TTX), to MAM rats) completely reversed theelevated DA neuron population activity and also normalized the augmentedamphetamine-induced locomotor behavior. The correlation of hippocampaldysfunction and the hyper-responsivity of the DA system is believed tounderlie the augmented response to amphetamine in MAM-treated animalsand psychosis in schizophrenia patients. See Lodge D. J. et al.Neurobiology of Disease (2007), 27(42), 11424-11430. The use ofMAM-treated rats in the above study may be suitable for use to assay theeffectiveness of the methods and compositions of the present inventionin treating schizophrenia or bipolar disorder (in particular, mania).For example, the methods and compositions of this invention may beevaluated, using MAM-treated animals, for their effects on the centralhippocampus (vHipp) regulation, on the elevated DA neuron populationactivity and on the hyperactive locomotor response to amphetamine in theMAM-treated animals.

In MAM-treated rats, hippocampal (HPC) dysfunction leads to dopaminesystem hyperactivity. A benzodiazepine-positive allosteric modulator(PAM), selective for the α5 subunit of the GABA_(A) receptor,SH-053-2′F—R—CH₃, is tested for its effects on the output of thehippocampal (HPC). The effect of SH-053-2′F—R—CH₃ on the hyperactivelocomotor response to amphetamine in MAM-treated animals is alsoexamined. The α5GABAAR PAM reduces the number of spontaneously active DAneurons in the ventral tegmental area (VTA) of MAM rats to levelsobserved in saline-treated rats (control group), both when administeredsystemically and when directly infused into the ventral HPC. Moreover,HPC neurons in both saline-treated and MAM-treated animals showdiminished cortical-evoked responses following the α5GABAAR PAMtreatment. In addition, the increased locomotor response to amphetamineobserved in MAM-treated rats is reduced following the α5GABA_(A)R PAMtreatment. See Gill K. M et al. Neuropsychopharmacology (2011), 1-9. Theuse of MAM-treated rats in the above study may be suitable for use inthe present invention to assay the effectiveness of the methods andcompositions of the invention in treating schizophrenia or bipolardisorder (in particular, mania). For example, the methods andcompositions of this invention maybe evaluated, using MAM-treatedanimals, for their effects on the output of the hippocampal (HPC) and onthe hyperactive locomotor response to amphetamine in the MAM-treatedanimals.

Administration of MAM to pregnant rats on embryonic day 15 (E15)severely impairs spatial memory or the ability to learn the spatiallocation of four items on an eight-arm radial maze in the offspring. Inaddition, embryonic day 17 (E17) MAM-treated rats are able to reach thelevel of performance of control rats at the initial stages of training,but are unable to process and retrieve spatial information when a 30-mindelay is interposed, indicating a significant impairment in workingmemory. See Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287-292.Such animal models of schizophrenia may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice isanother animal model useful in this invention. Agents are administeredto mice at a desired dose level (e.g., via intraperitonealadministration). Subsequently, e.g., thirty minutes later, experimentalmice are challenges with apomorphine (e.g., with 1 mg/kg sc). Fiveminutes after the apomorphine injection, the sniffing-licking-gnawingsyndrome (stereotyped behavior) and climbing behavior induced byapomorphine are scored and recorded for each animal. Readings can berepeated every 5 min during a 30-min test session. Scores for eachanimal are totaled over the 30-min test session for each syndrome(stereotyped behavior and climbing). If an effect reached at least of50% inhibition, and ID₅₀ value (95% confidence interval) is calculatedusing a nonlinear least squares calculation with inverse prediction.Mean climbing and stereotype scores can be expressed as a percent ofcontrol values observed in vehible treated (e.g., saline-treated) micethat receive apomorphine. See Grauer S. M. et al. Psychopharmacology(2009) 204, 37-48. This mice model may be used to assay theeffectiveness of the methods and compositions of the invention intreating schizophrenia or bipolar disorder (in particular, mania).

The efficacy of the methods and compositions of this invention intreating schizophrenia may also be assessed in animal models ofschizophrenia or bipolar disorder (in particular, mania), as well ashuman subjects with schizophrenia, using a variety of cognitive testsknown in the art, as discussed above.

Amyotrophic Lateral Sclerosis (ALS)

This invention additionally provides methods and compositions fortreating ALS using an SV2A inhibitor or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof, alone or incombination with valproate or an analog, derivative or pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof. Incertain embodiments, treatment comprises improving cognitive function inpatients with ALS. In certain embodiments, treatment comprises slowingor delaying the progression of ALS. In certain embodiments, treatmentcomprises reducing the rate of decline of cognitive function associatedwith ALS. In certain embodiments, treatment comprises preventing orslowing the progression, of ALS. In certain embodiments, treatmentcomprises alleviation, amelioration or slowing the progression, of oneor more symptoms associated with ALS. In certain embodiments, thesymptom to be treated is cognitive impairment. The methods andcompositions may be used for human patients in clinical applications intreating ALS. The dose of the composition and dosage interval for themethod is, as described herein, one that is safe and efficacious inthose applications.

In addition to the degeneration of motor neurons, ALS is characterizedby neuronal degeneration in the entorhinal cortex and hippocampus,memory deficits, and neuronal hyperexcitability in different brain areassuch as the cortex.

The efficacy of the methods and compositions of this invention intreating ALS, or cognitive impairment associated with ALS, may also beassessed in animal models of ALS, as well as human subjects with ALS,using a variety of cognitive tests known in the art, as discussed above.

Cancer Therapy-Related Cognitive Impairment

This invention additionally provides methods and compositions fortreating cancer therapy-related cognitive impairment using an SV2Ainhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof, alone or in combination with valproate oran analog, derivative or pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof. In certain embodiments,treatment comprises improving cognitive function in patients with cancertherapy-related cognitive impairment. In certain embodiments, treatmentcomprises slowing or delaying the progression of cancer therapy-relatedcognitive impairment. In certain embodiments, treatment comprisesreducing the rate of decline of cognitive function associated withcancer therapy-related cognitive impairment. In certain embodiments,treatment comprises preventing or slowing the progression, of cancertherapy-related cognitive impairment. In certain embodiments, treatmentcomprises alleviation, amelioration or slowing the progression, of oneor more symptoms associated with cancer therapy-related cognitiveimpairment. The methods and compositions may be used for human patientsin clinical applications in treating cancer therapy-related cognitiveimpairment. The dose of the composition and dosage interval for themethod is, as described herein, one that is safe and efficacious inthose applications.

Therapies that are used in cancer treatment, including chemotherapy,radiation, or combinations thereof, can cause cognitive impairment inpatients, in such functions as memory, learning and attention.Cytotoxicity and other adverse side-effects on the brain of cancertherapies are the basis for this form of cognitive impairment, which canpersist for decades. (Dietrich et al., Oncologist 13:1285-95, 2008;Soussain et al., Lancet 374:1639-51, 2009).

Cognitive impairment following cancer therapies reflects dysfunction infrontal cortical and hippocampal circuits that are essential for normalcognition. In animal models, exposure to either chemotherapy orradiation adversely affects performance on tests of cognitionspecifically dependent on these brain systems, especially thehippocampus (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al.,Neurobiol. Learning and Mem. 93:487-494, 2010). Thus, drugs targetingthese cortical and hippocampal systems could be neuroprotective inpatients receiving cancer therapies and efficacious in treating symptomsof cognitive impairment that may last beyond the interventions used ascancer therapies.

Animal models serve as an important resource for developing andevaluating treatments for cancer therapy-related cognitive impairment.Features that characterize cancer therapy-related cognitive impairmentin animal models typically extend to cancer therapy-related cognitiveimpairment in humans. Thus, efficacy in such animal models is expectedto be predictive of efficacy in humans. Various animal models of cancertherapy-related cognitive impairment are known in the art.

Examples of animal models of cancer therapy-related cognitive impairmentinclude treating animals with anti-neoplastic agents such ascyclophosphamide (CYP) or with radiation, e.g., ⁶⁰Co gamma-rays. (Kim etal., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learningand Mem. 93:487-494, 2010). The cognitive function of animal models ofcancer therapy-related cognitive impairment may then be tested withcognitive tests to assay the effectiveness of the methods andcompositions of the invention in treating cancer therapy-relatedcognitive impairment. The efficacy of the methods and compositions ofthis invention in treating cancer therapy-related cognitive impairment,as well as human subjects with cancer therapy-related cognitiveimpairment, using a variety of cognitive tests known in the art, asdiscussed above.

Parkinson's Disease (PD)

Parkinson's disease (PD) is a neurological disorder characterized by adecrease of voluntary movements. The afflicted patient has reduction ofmotor activity and slower voluntary movements compared to the normalindividual. The patient has characteristic “mask” face, a tendency tohurry while walking, bent over posture and generalized weakness of themuscles. There is a typical “lead-pipe” rigidity of passive movements.Another important feature of the disease is the tremor of theextremities occurring at rest and decreasing during movements.

Parkinson's disease, the etiology of which is unknown, belongs to agroup of the most common movement disorders named parkinsonism, whichaffects approximately one person per one thousand. These other disordersgrouped under the name of parkinsonism may result from viral infection,syphilis, arteriosclerosis and trauma and exposure to toxic chemicalsand narcotics. Nonetheless, it is believed that the inappropriate lossof synaptic stability may lead to the disruption of neuronal circuitsand to brain diseases. Whether as the result of genetics, drug use, theaging process, viral infections, or other various causes, dysfunction inneuronal communication is considered the underlying cause for manyneurologic diseases, such as PD (Myrrhe van Spronsen and Casper C.Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010 10, 207-214).

Regardless of the cause of the disease, the main pathologic feature isdegeneration of dopaminergic cells in basal ganglia, especially insubstantia nigra. Due to premature death of the dopamine containingneurons in substantia nigra, the largest structure of the basal ganglia,the striatum, will have reduced input from substantia nigra resulting indecreased dopamine release. The understanding of the underlyingpathology led to the introduction of the first successful treatmentwhich can alleviate Parkinson's disease. Virtually all approaches to thetherapy of the disease are based on dopamine replacement. Drugscurrently used in the treatment can be converted into dopamine aftercrossing the blood brain barrier, or they can boost the synthesis ofdopamine and reduce its breakdown. Unfortunately, the main pathologicevent, degeneration of the cells in substantia nigra, is not helped. Thedisease continues to progress and frequently after a certain length oftime, dopamine replacement treatment will lose its effectiveness.

This invention provides methods and compositions for treating PD usingan SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof, alone or in combination withvalproate or a derivative or an analog or a pharmaceutically acceptablesalt thereof. In certain embodiments, treatment comprises preventing orslowing the progression of PD. In certain embodiments, treatmentcomprises alleviation, amelioration, or slowing the progression of oneor more symptoms associated with PD. In certain embodiments, the symptomto be treated is cognitive impairment. For example, methods andcompositions of the disclosure can be used to improve themotor/cognitive impairments symptomatic of Parkinson's disease.Moreover, methods and compositions of the disclosure may be useful fortreating the memory impairment symptomatic of Parkinson's disease.

There are a number of animal models for PD. Exemplary animal models forPD include the reserpine model, the methamphetamine model, the6-hydroxydopamine (6-OHDA) model, the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, the paraquat(PQ)-Maneb model, the rotenone model, the 3-nitrotyrosine model andgenetic models using transgenic mice. Transgenic models include micethat over express α-synuclein, express human mutant forms ofα-synuclein, or mice that express LRKK2 mutations. See review of thesemodels by Ranjita B. et al. (Ranjita B. et al. BioEssays 2002, 24,308-318). Additional information regarding these animal models isreadily available from Jackson Laboratories (see alsohttp://research.jax.org/grs/parkinsons.html), as well as in numerouspublications disclosing the use of these validated models.

The efficacy of the methods and compositions of this invention intreating PD, or cognitive impairment associated with PD, may be assessedin any of the above animal models of PD, as well as human subjects withPD, using a variety of cognitive tests known in the art, as discussedabove.

Autism

“Autism”, as used herein, refers to an autism spectrum disordercharacterized by a neural development disorder leading to impairedsocial interaction and communication by restricted and repetitivebehavior. “Autism Spectrum Disorder” refers to a group of developmentaldisabilities that includes: autism; Asperger syndrome; pervasivedevelopmental disorder not otherwise specified (PDD-NOS or atypicalautism); Rett syndrome; and childhood disintegrative disorder.

Autism is a neurodevelopmental disorder characterized by dysfunction inthree core behavioral dimensions: repetitive behaviors, social deficits,and cognitive deficits. The repetitive behavior domain involvescompulsive behaviors, unusual attachments to objects, rigid adherence toroutines or rituals, and repetitive motor mannerisms such asstereotypies and self-stimulatory behaviors. The social deficitdimension involves deficits in reciprocal social interactions, lack ofeye contact, diminished ability to carry on conversation, and impaireddaily interaction skills. The cognitive deficits can include languageabnormalities. Autism is a disabling neurological disorder that affectsthousands of Americans and encompasses a number of subtypes, withvarious putative causes and few documented ameliorative treatments. Thedisorders of the autistic spectrum may be present at birth, or may havelater onset, for example, at ages two or three. There are no clear cutbiological markers for autism. Diagnosis of the disorder is made byconsidering the degree to which the child matches the behavioralsyndrome, which is characterized by poor communicative abilities,peculiarities in social and cognitive capacities, and maladaptivebehavioral patterns. The dysfunction in neuronal communication isconsidered one of the underlying causes for autism (Myrrhe van Spronsenand Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10,207-214).

This invention provides methods and compositions for treating autismusing an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof, alone or in combination withvalproate or a derivative or an analog or a pharmaceutically acceptablesalt thereof. In certain embodiments, treatment comprises preventing orslowing the progression of autism. In certain embodiments, treatmentcomprises alleviation, amelioration, or slowing the progression of oneor more symptoms associated with autism. In certain embodiments, thesymptom to be treated is cognitive deficit. For example, methods andcompositions of the disclosure can be used to improve themotor/cognitive deficits symptomatic of autism.

The valproic acid (VPA) rat model of autism using in vitroelectrophysiological techniques, established by Rodier et al. (Rodier,P. M. et al. Reprod. Toxicol. 1997, 11, 417-422) is one of the mostexhaustively established insult-based animal models of autism and isbased on the observation that pregnant women treated with VPA in the1960s, during a circumscribed time window of embryogenesis, had a muchhigher risk of giving birth to an autistic child than the normalpopulation. Offspring of VPA-exposed pregnant rats show severalanatomical and behavioral symptoms typical of autism, such as diminishednumber of cerebellar Purkinje neurons, impaired social interaction,repetitive behaviors as well as other symptoms of autism, includingenhanced fear memory processing. See, Rinaldi T. et al. Frontiers inNeural Circuits, 2008, 2, 1-7. The efficacy of the methods andcompositions of this invention in treating autism, or cognitive deficitsassociated with autism, may be assessed in the VPA-treated rat model ofautism, as well as human subjects with autism, using a variety ofcognitive tests known in the art, as discussed above.

Mental Retardation

Mental retardation is a generalized disorder characterized bysignificantly impaired cognitive function and deficits in adaptivebehaviors. Mental retardation is often defined as an IntelligenceQuotient (IQ) score of less than 70. Inborn causes are among manyunderlying causes for mental retardation. The dysfunction in neuronalcommunication is also considered one of the underlying causes for mentalretardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol.Neurosci. Rep. 2010, 10, 207-214).

In some instances, mental retardation includes, but are not limited to,Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, FragileX syndrome, Klinefelter's syndrome, neurofibromatosis congenitalhypothyroidism, Williams syndrome, phenylketonuria (PKU),Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermidsyndrome, Mowat-Wilson syndrome, ciliopathy, Lowe syndrome and sideriumtype X-linked mental retardation. Down syndrome is a disorder thatincludes a combination of birth defects, including some degree of mentalretardation, characteristic facial features and, often, heart defects,increased infections, problems with vision and hearing, and other healthproblems. Fragile X syndrome is a prevalent form of inherited mentalretardation, occurring with a frequency of 1 in 4,000 males and 1 in8,000 females. The syndrome is also characterized by developmentaldelay, hyperactivity, attention deficit disorder, and autistic-likebehavior. There is no effective treatment for fragile X syndrome.

The present invention contemplates the treatment of mild mentalretardation, moderate mental retardation, severe mental retardation,profound mental retardation, and mental retardation severityunspecified. Such mental retardation may be, but is not required to be,associated with chromosomal changes, (for example Down Syndrome due totrisomy 21), heredity, pregnancy and perinatal problems, and othersevere mental disorders. This invention provides methods andcompositions for treating mental retardation an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof, alone or in combination with valproate or a derivativeor an analog or a pharmaceutically acceptable salt thereof. In certainembodiments, treatment comprises preventing or slowing the progressionof mental retardation. In certain embodiments, treatment comprisesalleviation, amelioration, or slowing the progression of one or moresymptoms associated with mental retardation. In certain embodiments, thesymptom to be treated is cognitive deficit/impairment. For example,methods and compositions of the disclosure can be used to improve themotor/cognitive impairments symptomatic of mental retardation.

Several animal models have been developed for mental retardation. Forexample, a knockout mouse model has been developed for Fragile Xsyndrome. Fragile X syndrome is a common form of mental retardationcaused by the absence of the FMR1 protein, FMRP. Two homologs of FMRPhave been identified, FXR1P and FXR2P. FXR2P shows high expression inbrain and testis, like FMRP. Both Fxr2 and Fmr1 knockout mice, andFmr1/Fxr2 double knockout mice are believed to be useful models formental retardation such as Fragile X syndrome. See, Bontekoe C. J. M. etal. Hum. Mol. Genet. 2002, 11 (5): 487-498. The efficacy of the methodsand compositions of this invention in treating mental retardation, orcognitive deficit/impairment associated with mental retardation, may beassessed in the these mouse models and other animal models developed formental retardation, as well as human subjects with mental retardation,using a variety of cognitive tests known in the art, as discussed above.

Compulsive Behavior (Obsessive Compulsive Disorder)

Obsessive compulsive disorder (“OCD”) is a mental condition that is mostcommonly characterized by intrusive, repetitive unwanted thoughts(obsessions) resulting in compulsive behaviors and mental acts that anindividual feels driven to perform (compulsion). Current epidemiologicaldata indicates that OCD is the fourth most common mental disorder in theUnited States. Some studies suggest the prevalence of OCD is between oneand three percent, although the prevalence of clinically recognized OCDis much lower, suggesting that many individuals with the disorder maynot be diagnosed. Patients with OCD are often diagnosed by apsychologist, psychiatrist, or psychoanalyst according to the Diagnosticand Statistical Manual of Mental Disorders, 4th edition text revision(DSM-IV-TR) (2000) diagnostic criteria that include characteristics ofobsessions and compulsions. Characteristics of obsession include: (1)recurrent and persistent thoughts, impulses, or images that areexperienced as intrusive and that cause marked anxiety or distress; (2)the thoughts, impulses, or images are not simply excessive worries aboutreal-life problems; and (3) the person attempts to ignore or suppresssuch thoughts, impulses, or images, or to neutralize them with someother thought or action. The person recognizes that the obsessionalthoughts, impulses, or images are a product of his or her own mind, andare not based in reality. Characteristics of compulsion include: (1)repetitive behaviors or mental acts that the person feels driven toperform in response to an obsession, or according to rules that must beapplied rigidly; (2) the behaviors or mental acts are aimed atpreventing or reducing distress or preventing some dreaded event orsituation; however, these behaviors or mental acts are not actuallyconnected to the issue, or they are excessive.

Individuals with OCD typically perform tasks (or compulsion) to seekrelief from obsession-related anxiety. Repetitive behaviors such ashandwashing, counting, checking, or cleaning are often performed withthe hope of preventing obsessive thoughts or making them go away.Performing these “rituals,” however, only provides temporary relief.People with OCD may also be diagnosed with a spectrum of other mentaldisorders, such as generalized anxiety disorder, anorexia nervosa, panicattack, or schizophrenia.

The dysfunction in neuronal communication is considered one of theunderlying causes for obsession disorder (Myrrhe van Spronsen and CasperC. Hoogenraad, Curr. Neural. Neurosci. Rep. 2010, 10, 207-214). Studiessuggest that OCD may be related to abnormal levels of a neurotransmittercalled serotonin. The first-line treatment of OCD consists of behavioraltherapy, cognitive therapy, and medications. Medications for treatmentinclude serotonin reuptake inhibitors (SRIs) such as paroxetine(Seroxat™, Xetanor™, ParoMerck™, Rexetin™), sertraline (Zoloft®,Stimuloton™), fluoxetine (Prozac®, Bioxetin™), escitalopram (Lexapro®),and fluvoxamine (Luvox®) as well as the tricyclic antidepressants, inparticular clomipramine (Anafranil®). Benzodiazepines are also used intreatment. As much as 40 to 60% of the patients, however, fail toadequately respond to the SRI therapy and an even greater proportion ofpatients fail to experience complete remission of their symptoms.

This invention provides methods and compositions for treating OCD usingan SV2A inhibitor or a pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof, alone or in combination withvalproate or a derivative or an analog or a pharmaceutically acceptablesalt thereof. In certain embodiments, treatment comprises preventing orslowing the progression of OCD. In certain embodiments, treatmentcomprises alleviation, amelioration, or slowing the progression of oneor more symptoms associated with OCD. In certain embodiments, thesymptom to be treated is cognitive deficit. For example, methods andcompositions of the disclosure can be used to treat the cognitivedeficits in OCD, and/or to improve cognitive function in patients withOCD. A quinpirole-sensitized rat model has been developed for OCD. Thecompulsive checking behavior of the quinpirole-sensitized rats issubject to interruption, which is an attribute characteristic of OCDcompulsions. The efficacy of the methods and compositions of thisinvention in treating OCD, or cognitive deficits associated with OCD,may be assessed in this rat model and other animal models developed forOCD, as well as human subjects with OCD, using a variety of cognitivetests known in the art, as discussed above.

Substance Addiction

Substance addiction (e.g., drug substance addiction, alcohol substanceaddiction) is a mental disorder. The substance addiction is nottriggered instantaneously upon exposure to substnace of abuse. Rather,it involves multiple, complex neural adaptations that develop withdifferent time courses ranging from hours to days to months (Kauer J. A.Nat Rev. Neurosci, 2007, 8, 844-858). The path to substance addictiongenerally begins with the voluntary use of one or more controlledsubstances, such as narcotics, barbiturates, methamphetamines, alcohol,nicotine, and any of a variety of other such controlled substances. Overtime, with extended use of the controlled substance(s), the voluntaryability to abstain from the controlled substance(s) is compromised dueto the effects of prolonged use on brain function, and thus on behavior.As such, substance addiction generally is characterized by compulsivesubstance craving, seeking and use that persist even in the face ofnegative consequences. The cravings may represent changes in theunderlying neurobiology of the patient which likely must be addressed ina meaningful way if recovery is to be obtained. Substance addiction isalso characterized in many cases by withdrawal symptoms, which for somesubstances are life threatening (e.g., alcohol, barbiturates) and inothers can result in substantial morbidity (which may include nausea,vomiting, fever, dizziness, and profuse sweating), distress, anddecreased ability to obtain recovery. For example, alcoholism, alsoknown as alcohol dependence, is one such substance addiction. Alcoholismis primarily characterized by four symptoms, which include cravings,loss of control, physical dependence and tolerance. These symptoms alsomay characterize substance addictions to other controlled substances.The craving for alcohol, as well as other controlled substances, oftenis as strong as the need for food or water. Thus, an alcoholic maycontinue to drink despite serious family, health and/or legalramifications.

Recent work exploring the effects of abusing alcohol, centralstimulants, and opiates on the central nervous system (CNS) havedemonstrated a variety of adverse effects related to mental health,including substance-induced impairments in cognition. See, Nyberg F.Cognitive Impairments in Drug Addicts, Chapter 9. In severallaboratories and clinics substantial damages of brain function are seento result from these drugs. Among the harmful effects of the abusingdrugs on brain are those contributing to accelerated obsolescence. Anobservation that has received special attention during recent years isthat chronic drug users display pronounced impairment in brain areasassociated with executive and memory function. A remarkedneuroadaptation caused by addictive drugs, such as alcohol, centralstimulants and opiates involves diminished neurogenesis in thesubgranular zone (SGZ) of the hippocampus. Indeed, it has been proposedthat decreased adult neurogenesis in the SGZ could modify thehippocampal function in such a way that it contributes to relapse and amaintained addictive behavior. It also raises the possibility thatdecreased neurogenesis may contribute to cognitive deficits elicited bythese abusing drugs.

This invention provides methods and compositions for treating substanceaddiction an SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof, alone or in combinationwith valproate or a derivative or an analog or a pharmaceuticallyacceptable salt thereof. In certain embodiments, treatment comprisespreventing or slowing the progression of substance addiction. In certainembodiments, treatment comprises alleviation, amelioration, or slowingthe progression of one or more symptoms associated with substanceaddiction. In certain embodiments, the symptom to be treated iscognitive impairment. For example, methods and compositions of thedisclosure can be used to treat the cognitive impairment and/or toimprove cognitive function in patients with substance addiction.

Several animal models have been developed to study substance addiction.For example, a genetically selected Marchigian Sardinianalcohol-preferring (msP) rat models was developed to study theneurobiology of alcoholism. See, Ciccocioppo R. et al. Substanceaddiction Biology 2006, 11, 339-355. The efficacy of the methods andcompositions of this invention in treating substance addiction, orcognitive impairment associated with substance addiction, may also beassessed in animal models of substance addiction, as well as humansubjects with substance addiction, using a variety of cognitive testsknown in the art, as discussed above.

SV2A Inhibitor

“Synaptic vesicle protein-2 (SV2)” is a family of synaptic vesicleproteins, which consists of three members, designated SV2A, SV2B, andSV2C. SV2A is the most widely distributed family member, being expressedubiquitously in the brain. The proteins are integral membrane proteinsand have a low-level homology (20-30%) to the twelve transmembranefamily of bacterial and fungal transporter proteins that transportsugar, citrate, and xenobiotics (Bajjalieh et al., Science. 257:1271-1273. (1992)). SV2 family proteins are present in the brain andendocrine cells, and further are present in all synaptic and endocrinevesicles. SV2 proteins are reported to play a role in normal synapticfunction, and functions in a maturation step of primed vesicles thatconverts the vesicles into a Ca(²⁺)— and synaptotagmin-responsive state(Sudhof et al., 2009). Functionally, SV2 proteins are reported toenhance synaptic currents and increase the probability of transmitterrelease by maintaining the size of the readily releasable pool ofvesicles (Custer et al., 2006).

“SV2A inhibitor” refers to any agent, substance or compound that bindsto SV2A and reduces synaptic function by reducing pre-synaptic vesiclerelease (See, e.g., Noyer et al. 1995; Fuks et al. 2003; Lynch et al.2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yanget al., 2007; Meehan, “Levetiracetam has an activity-dependent effect oninhibitory transmission,” Epilepsia, 2012 Jan. 31; and Example 8 of WO2001/62726, all of which are specifically incorporated herein byreference.) A substance, or a compound or an agent is an SV2A inhibitoreven if it does not itself bind to SV2A, as long as it causes, oraffects the ability of, another compound or agent to bind SV2A or reducesynaptic function by reducing pre-synaptic vesicle release. SV2Ainhibitors, suitable for use in the present invention, include the SV2Ainhibitor formulas and specific SV2A inhibitors described herein, andtheir derivatives, analogs, hydrates, polymorphs, prodrugs, salts (e.g.,pharmaceutically acceptable salts), and solvates.

Among the SV2A inhibitors or pharmaceutically acceptable salts,hydrates, solvates, polymorphs, and thereof that are useful in themethods and compositions of this invention are those disclosed, forexample, U.S. patent application Ser. No. 12/580,464, InternationalPatent Application PCT/US2009/005647, U.S. Patent Application61/105,847, U.S. Patent Application 61/152,631, and U.S. PatentApplication 61/175,536. However, any SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be used in the methods and compositions of theinvention. In some embodiments, the SV2A inhibitor is selected from thegroup of SV2A inhibitors referred to in International PatentApplications WO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595;WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658;WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549; 7,244,747;5,334,720; 4,696,943; 4,696,942; U.S. Patent Application PublicationNumbers 20090312333; 20090018148; 20080081832; 2006258704; and UK PatentNumbers 1,039,113; and 1,309,692 or their pharmaceutically acceptablesalts, hydrates, solvates, polymorphs or prodrugs. Other SV2A inhibitorsmay also be used in this invention. Applicants also refer to methods ofpreparing these compounds found in the documents cited above. Othersynthetic methods may also be used. These methods are well known tothose skilled in the art.

In some embodiments of this invention, the SV2A inhibitor is selectedfrom the group consisting of levetiracetam, brivaracetam, andseletracetam or derivatives or analogs or pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, or prodrugs thereof.

In some embodiments of this invention, the SV2A inhibitor islevetiracetam or salts, solvates, hydrates, polymorphs or prodrugsthereof. Levetiracetam refers to the International Union of Pure andApplied Chemistry (IUPAC) name of the compound(2S)-2-(2-oxopyrrolidin-1-yl)butanamide). Levetiracetam is a widely usedantiepileptic drug. Levetiracetam binds to a specific site in the CNS:the synaptic vesicle protein 2A (SV2A) (See. e.g., Noyer et al. 1995;Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006) and hasfurther been shown to directly inhibit synaptic activity andneurotransmission by inhibiting presynaptic neurotransmitter release(Yang et al., 2007).

Among the SV2A inhibitors useful for the methods and compositions ofthis invention are the following:

i) International Patent Application WO 2001/062726:

A compound having the formula I or a pharmaceutically acceptable saltthereof,

wherein X is —CA¹NR⁵R⁶ or —CA¹OR⁷ or —CA¹-R⁸ or CN;

A¹ and A² are independently oxygen, sulfur or —NR⁹;

R¹ is hydrogen, alkyl, aryl or —CH₂—R^(1a) wherein R^(1a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R², R³ and R⁴ are the same or different and each is independentlyhydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido,carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl,ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative,amino derivative, acyl derivative, sulfonyl derivative or sulfinylderivative;

R^(2a), R^(3a) and R^(4a) are the same or different and each isindependently hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;

R⁵, R⁶, R⁷ and R⁹ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or athio derivative;

with the provisos that at least one of as R², R³, R⁴, R^(2a), R^(3a) andR^(4a) is other than hydrogen; and that when the compound is a mixtureof all possible isomers, X is —CONR⁵R⁶, A² is oxygen and R¹ is hydrogen,methyl, ethyl or propyl then substitution on the pyrollidine ring isother than mono-, di-, or tri-methyl or mono-ethyl; and that when R¹,R², R⁴, R^(2a), R^(3a) and R^(4a) are each hydrogen, A² is oxygen and Xis CONR⁵R⁶ then R³ is different from carboxy, ester, amido, substitutedoxo-pyrrolidine, hydroxy, oxy derivative, amino, amino derivatives,methyl, naphthyl, phenyl optionally substituted by oxy derivatives or inthe para position by an halogen atom.

In the definitions set forth below, unless otherwise stated, R¹¹ and R¹²are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein is defined as including —O—R¹¹groups wherein R¹¹ is as defined above except for “oxy derivative”.Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy,oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy,arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy,allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy,2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative” as used herein, is defined as including—S—R¹¹ groups wherein R¹¹ is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative” as used herein, is defined as including—NHR¹¹ or —NR¹¹R¹² groups wherein R¹¹ and R¹² are as defined above.Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- andarylamino or mixed amino.

The term “acyl derivative” as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R¹¹—CO—, wherein R¹¹ is as defined above and may also behydrogen. Non-limiting examples are formyl, acetyl, propionyl,isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl,crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl,4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

The term “sulfonyl derivative” as used herein, is defined as including agroup of the formula —SO₂—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfonyl derivative”. Non-limiting examples are alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative” as used herein, is defined as including agroup of the formula —SO—R¹¹, wherein R¹¹ is as defined above except for“sulfinyl derivative”. Non-limiting examples are alkylsulfinyl,alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and containing 1-20 carbon atoms,preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atomsfor cycloalkyl (in these two preferred cases, unless otherwisespecified, “lower alkyl”). Alkyl moieties may optionally be substitutedby 1 to 5 substituents independently selected from the group consistingof halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl,acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy,ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thioderivative, oxyester, oxyamido, heterocycle, vinyl, C1-5-alkoxy,C6-10-aryloxy and C6-10-aryl.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, and 2,2,2-trimethylethyl each optionally substituted by atleast one substituent selected from the group consisting of halogen,hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl,trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

The term “alkenyl” as used herein, is defined as including both branchedand unbranched, unsaturated hydrocarbon radicals having at least onedouble bond such as ethenyl (=vinyl), 1-methyl-1-ethenyl,2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl,2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl,3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, and the like and beingoptionally substituted by at least one substituent selected from thegroup consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryland heterocycle such as mono- and di-halo vinyl where halo is fluoro,chloro or bromo.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl and heterocycle, such as haloethynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g., “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl” as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of 1-3 rings andcontaining 6-30 carbon atoms by removal of one hydrogen, such as phenyland naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, hydroxy, thiol, amino, nitro,cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester,ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl,alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, C1-6-alkoxy,C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. Aryl radicals are preferablymonocyclic containing 6-10 carbon atoms. Preferred aryl groups arephenyl and naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl and phenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “azido”, as used herein, represents a group of the formula —N₃.

The term “carboxy”, as used herein, represents a group of the formula—COOH. The term “sulfonic acid”, as used herein, represents a group ofthe formula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “ester”, as used herein is defined as including a group offormula —COO—R¹¹ wherein R¹¹ is as defined above except oxy derivative,thio derivative or amino derivative.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH₂ or—CONHR¹¹ or —CONR¹¹R¹² wherein R¹¹ and R¹² are as defined above.

The term “heterocycle”, as used herein is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Non-limitingexamples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl,isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thieno (2,3-b) furanyl, furopyranyl, benzofuranyl,benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, orbenzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl,acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl,isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, and pyrazolopyrimidinyl optionally substituted byalkyl or as described above for the alkyl groups. Non-limiting examplesof non aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino,morpholinyl, 1-oxaspiro(4.5) dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl,sugar moieties (i.e. glucose, pentose, hexose, ribose, fructose, whichmay also be substituted) or the same which can optionally be substitutedwith any suitable group, including but not limited to one or moremoieties selected from lower alkyl, or other groups as described abovefor the alkyl groups. The term “heterocycle” also includes bicyclic,tricyclic and tetracyclic, spiro groups in which any of the aboveheterocyclic rings is fused to one or two rings independently selectedfrom an aryl ring, a cyclohexane ring, a cyclohexene ring, acyclopentane ring, a cyclopentene ring or another monocyclicheterocyclic ring or where a monocyclic heterocyclic group is bridged byan alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl,7-oxabicyclo(2.2.1) heptanyl, 8-azabicyclo(3.2.1)octanyl.

In the above definitions it is to be understood that when a substituentsuch as R², R³, R⁴, R^(2a), R^(3a), R^(4a), R⁵, R⁶, R⁷, R⁸ is attachedto the rest of the molecule via a heteroatom or a carbonyl, a straight-or branched chain, C1-12-, preferably C1-4-alkylene or C2-12, preferablyC2-4-alkenylene or -alkynylene bridge may optionally be interposedbetween the heteroatom or the carbonyl and the point of attachment tothe rest of the molecule.

Preferred examples of X are —COOR⁷ or —CONR⁵R⁶, wherein R⁵, R⁶ and R⁷are preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl.

Preferably X is carboxy or —CONR⁵R⁶, wherein R⁵ and R⁶ are preferablyhydrogen, C1-4-alkyl, phenyl or alkylphenyl, especially —CONH₂.

Preferably A¹ and A² are each oxygen.

Preferably R¹ is hydrogen, alkyl, especially C1-12 alkyl, particularlylower alkyl or aryl especially phenyl.

Examples of preferred R¹ groups are methyl, ethyl, propyl, isopropyl,butyl, iso- or ter-butyl, 2,2,2-trimethylethyl each optionally attachedvia a methylene bridge or the same substituted by at least one halogenatom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

R¹ as ethyl is especially preferred.

Preferably R² and R^(2a) are independently hydrogen, halogen or alkyl,especially lower alkyl.

Examples of preferred R² and R^(2a) groups are independently hydrogen,halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl,2,2,2-trimethylethyl or the same substituted by at least one halogenatom such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

Especially at least one and most preferably both of R² and R^(2a) arehydrogen.

Preferably R^(3a), R⁴ and R^(4a) are independently hydrogen, alkyl,especially methyl or ethyl or aryl especially phenyl or aralkyl,especially benzyl.

Examples of preferred R^(3a), R⁴ and R^(4a) groups are independentlyhydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso orter-butyl, 2,2,2-trimethylethyl or the same substituted by at least onehalogen atom such as trifluoromethyl, trichloromethyl,2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl.

Especially at least one and most preferably both of R⁴ and R^(4a) arehydrogen.

R^(3a) is particularly hydrogen or alkyl, especially lower alkyl and ismost preferably hydrogen.

Preferably R³ is hydrogen, C1-12-alkyl, especially C1-6-alkyl, eachoptionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ringeither directly or via a thio, sulfinyl, sulfonyl, carbonyl oroxycarbonyl group and optionally, a C1-4-alkylene bridge, particularlymethylene; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyleach optionally substituted by one or more halogens; azido; cyano;amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyleach optionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl and phenyl and attached to the ring either directlyor via a carbonyl group or a C1-4-alkylene bridge, particularlymethylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl eachoptionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino,azido, phenyl and nitro and each attached to the ring either directly orvia an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group andoptionally additionally a C1-4-alkylene bridge, particularly methylene.

Also, preferably, R³ is C1-6-alkyl optionally substituted by one or moresubstituents selected from halogen, thiocyanato, azido, alkoxy,alkylthio, phenylsulfonyl; nitrooxy; C2-3-alkenyl or -alkynyl eachoptionally substituted by one or more halogens or by acetyl; tetrazolyl,pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyleach optionally substituted by one or more substituents selected fromhalogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, amino, azido, phenyland nitro and each attached to the ring either directly or via asulfonyloxy and optionally additionally a C1-4-alkylene bridge,particularly methylene.

Other examples of preferred R³ groups are hydrogen, halogen or methyl,ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethylor the same substituted by at least one halogen atom such astrifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl,1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

R³ is especially C1-4-alkyl optionally substituted by one or moresubstituents selected from halogen, thiocyanato or azido; C2-5-alkenylor -alkynyl, each optionally substituted by one or more halogens;thienyl; or phenyl optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl, C1-6 haloalkyl or azido.

Further examples of preferred R³ groups are C1-6 alkyl and C2-6haloalkenyl.

Preferably R⁵ and R⁶ are independently hydrogen, methyl, ethyl, propyl,isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, especiallyhydrogen or methyl.

Especially at least one and most preferably both of R⁵ and R⁶ arehydrogen.

Preferably R⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl orthe same substituted by at least one halogen atom such astrifluoromethyl, chlorophenyl.

Preferably R⁷ is hydrogen, methyl or ethyl especially hydrogen.

Preferably R⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isoor ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the samesubstituted by at least one halogen atom such as trifluoromethyl,chlorobenzyl.

Preferably R⁸ is hydrogen or methyl.

Combinations of one or more of these preferred compound groups areespecially preferred.

A particular group of compounds of formula I (Compounds 1A) comprisesthose wherein,

A² is oxygen;

X is —CONR⁵R⁶ or —COOR⁷ or —CO—R⁸ or CN;

R¹ is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R², R³, R⁴, are the same or different and each is independently hydrogenor halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonylderivative, a sulfinyl derivative, an amino derivative, carboxy, ester,ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, a thioderivative, alkyl, alkoxy, oxyester, oxyamido, aryl, an oxy derivative,heterocycle, vinyl and R³ may additionally represent C2-5 alkenyl, C2-5alkynyl or azido each optionally substituted by one or more halogen,cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl; orphenylsulfonyloxy whereby any phenyl moiety may be substituted by one ormore halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

R^(2a), R^(3a) and R^(4a) are hydrogen;

R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen,hydroxy, alkyl, aryl, heterocycle or oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle,alkylthio or thio derivative.

Within these Compounds 1A, R¹ is preferably methyl, ethyl, propyl,isopropyl, butyl, or isobutyl; most preferably methyl, ethyl orn-propyl.

R² and R⁴ are preferably independently hydrogen or halogen or methyl,ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, areeach hydrogen.

R³ is preferably C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl,azido, each optionally substituted by one or more halogen, cyano,thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl; phenyl;phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl,pyrrole, pyridine, whereby any phenyl moiety may be substituted by oneor more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

X is preferably —COOH or —COOMe or —COOEt or —CONH₂; most preferably—CONH₂.

A further particular group of compounds of formula I (Compounds 1B)comprises those wherein,

X is —CA¹NH₂, —CA¹NHCH₃ or —CA¹N (CH₃)₂;

R¹ is alkyl or phenyl;

R³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl,amido, aryl, heterocycle; or

R³ is CH₂R¹⁰ wherein R¹⁰ is hydrogen, cycloalkyl, oxyester,oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl,nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio,alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy ortrifluoroethyl;

R^(3a) is hydrogen, alkyl or aryl (especially with the proviso that whenR^(3′) is hydrogen, R³ other than methyl);

or R³R^(3a) form a cycloalkyl;

-   -   and R², R^(2a), R⁴ and R^(4a) are each hydrogen.

Within the compounds of formula I,

R¹ is preferably alkyl especially C1-12-more particularly C1-6-alkyl andis most preferably ethyl;

R², R^(2a), R^(3a) and R^(4a) are preferably hydrogen;

R³ is preferably selected from hydrogen; C1-12-alkyl, especiallyC1-6-alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato or alkoxy andattached to the ring either directly or via a thio, sulfinyl, sulfonyl,carbonyl or oxycarbonyl group and optionally additionally aC1-4-alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl,especially C2-3-alkenyl or -alkynyl, each optionally substituted by oneor more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienylor piperazinyl each optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl and phenyl and attached to the ringeither directly or via a carbonyl group or a C1-4-alkylene bridge,particularly methylene; naphthyl; or phenyl, phenylalkyl orphenylalkenyl each optionally substituted by one or more substituentsselected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy,C1-6-alkylthio, amino, azido, phenyl and nitro and each attached to thering either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl orcarbonyloxy group and optionally additionally a C1-4-alkylene bridge,particularly methylene;

R^(3a) is preferably hydrogen or C1-4-alkyl;

R⁴ and R^(4a) are preferably, independently hydrogen, C1-4-alkyl, phenylor benzyl.

A further group of compounds of formula I (Compounds 1C) comprises thosein racemic form wherein, when X is —CONR⁵R⁶ and R¹ is hydrogen, methyl,ethyl or propyl, then substitution on the pyrrolidine ring is other thanmono-, di-, or tri-methyl or mono-ethyl.

A further group of compound of formula I (Compounds 1D) comprises thosein racemic form wherein, when X is —CONR⁵R⁶ and R¹ is hydrogen orC1-6-alkyl, C2-6-alkenyl or -alkynyl or cycloalkyl, each unsubstituted,then substitution in the ring is other than by alkyl, alkenyl oralkynyl, each unsubstituted.

A further particular group of compounds of formula I (Compounds IE)comprises those wherein,

X is —CA¹NH₂;

R¹ is H;

R³ is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5halogen atoms, n-propyl optionally substituted by 1 to 5 halogen atoms,vinyl optionally substituted by one or two methyl, and/or 1 to 3 halogenatoms, acetylene optionally substituted by C1-4-alkyl, phenyl orhalogen;

R^(3a) is hydrogen or halogen, preferably fluorine;

and R², R^(2a), R⁴ and R^(4a) are each hydrogen;

as their racemates or in enantiomerically enriched form, preferably thepure enantiomers.

A further particular group of compounds of formula I (Compounds 1F)comprises those wherein,

X is —CA¹NH₂;

R¹ is H;

R³ is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted byazido, oxynitro, 1 to 6 halogen atoms;

R^(3a) is hydrogen or halogen, preferably fluorine;

and R², R^(2a), R⁴ and R^(4a) are each hydrogen; as their racemates orin enantiomerically enriched form, preferably the pure enantiomers.

In all the above mentioned scopes when the carbon atom to which R¹ isattached is asymmetric it is preferably in the “S”-configuration.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-(2-oxo-4-phenyl-1-pyrrplidinyl)butanamide;-   (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl    4-methylbenzenesulfonate;-   (2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidinyl]butanamide;-   2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl    nitrate;-   (2S)-2-[2-oxo-4-(1H-tetraazol-1-ylmethyl)-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide;-   2-{2-oxo-4-[(phenylsulfonyl)methyl]-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[(4S)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(2-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-vinylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;-   2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[2-oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-[1,1′-biphenyl]-4-yl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-{4-[(methylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxo-1-pyrrolidinyl]pentanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide;-   (2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]-N-methylbutanamide;-   (2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide;-   2-{4-[(Z)-2-fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(2-methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide;-   2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-{2-oxo-4-[2-(trifluoromethyl)phenyl]-1-pyrrolidinyl}butanamide;-   2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-{4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1-pyrrolidinyl}butanamide;-   2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(2-furyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(3,5-dibromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(4-ethynyl-2-oxo-1-pyrrolidinyl) butanamide;-   2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-pyrrolidinyl]butanamide;-   2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-[(4R)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[2-oxo-4-(1H-pyrrol-1-yl)-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-[4-(2-iodopropyl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;-   (2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide;-   (2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide;-   (2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide;-   (2R)-2-[4-(2,2-dichlorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-[(4S)-4-(2,2-difluoropropyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)pentanamide;-   3-cyclopropyl-2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4-yl)propanamide;-   2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentenamide;-   (2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

including all isomeric forms and mixtures thereof or a pharmaceuticallyacceptable salt thereof.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;-   (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;-   (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide.

ii) International Patent Application WO 2002/094787:

Compounds of the formula I

wherein n represents 0 or 1 whereby R¹ is not existent when n=0 and R¹is existent when n=1;

A¹ represents an oxygen or a sulfur atom;

X is —CONR⁷R⁸, —COOR⁹, —CO—R¹⁰ or CN;

R¹ when existent, R², R³, R⁴ and R⁵ are the same or different and eachis independently hydrogen, halogen, hydroxy, thiol, amino, nitro,nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide,alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxyderivative, thio derivative, amino derivative, acyl derivative, sulfonylderivative or sulfinyl derivative,

provided that at least one of the substituents R chosen from R¹ whenexistent, R², R³, R⁴ or R⁵ is not hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

R⁷, R⁸ and R⁹ are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; and

R¹⁰ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or athio derivative;

their pharmaceutically acceptable salts, geometrical isomers (includingcis and trans, Z and E isomers), enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one substituent R¹ to R⁵ is differentfrom hydrogen. Some non-substituted compounds are referred to in U.S.Pat. Nos. 5,468,733 and 5,516,759. U.S. Pat. No. 5,468,733 refers tonon-ring substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinylderivatives as inhibitors of the oncogene Ras protein. In particular,these compounds block the ability of Ras to transform normal cells tocancer cells, and therefore can be included in several chemotherapeuticcompositions for treating cancer.

U.S. Pat. No. 5,516,759 refers to non-ring substituted2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivativespresent at the N-terminus of dodecapeptides possessing LHRH (luteinizinghormone-releasing hormone) antagonistic activity. Such LHRH antagonistsare useful in the treatment of a variety of conditions in whichsuppression of sex steroids plays a key role including contraception,delay of puberty, treatment of benign prostatic hyperplasia a. o.

In the definitions set forth below, unless otherwise stated, R¹¹ and R¹²are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl. heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein, is defined as including—O—R¹¹ groups wherein R¹¹ is as defined above except for “oxyderivative”. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy,acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy,arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxysuch as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy,2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.

The term “thio derivative”, as used herein, is defined as including—S—R¹¹ groups wherein R¹¹ is as defined above except for “thioderivative”. Non-limiting examples are alkylthio, alkenylthio,alkynylthio and arylthio.

The term “amino derivative”, as used herein, is defined asincluding-NHR¹¹ or —NR¹¹R¹² groups wherein R¹¹ and R¹² are as definedabove. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-and arylamino or mixed amino.

The term “acyl derivative”, as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R¹¹—CO—, wherein R¹¹ is as defined above and may also behydrogen. Preferred are acyl derivatives of formula —COR¹¹ wherein R¹¹is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkenyl,heterocyle and aryl. Non-limiting examples are formyl, acetyl,propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl,cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl,furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl,oxamoyl.

The term “sulfonyl derivative”, as used herein, is defined as includinga group of the formula —SO₂—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfonyl derivative”. Non-limiting examples are alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative”, as used herein, is defined as includinga group of the formula —SO—R¹¹, wherein R¹¹ is as defined above exceptfor “sulfinyl derivative”. Non-limiting examples are alkylsulfinyl,alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and generally containing 1-20 carbonatoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms fornon-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these twopreferred cases, unless otherwise specified, “lower alkyl”), eachoptionally substituted by, preferably 1 to 5, substituents independentlyselected from the group consisting of halogen, hydroxy, thiol, amino,nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinylderivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl,sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester,oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy(preferably C6-10) and aryl (preferably C6-10).

Preferred are alkyl groups containing 1 to 7 carbon atoms, eachoptionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio,cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7cycloalkyl, each optionally substituted by one or more hydroxy, halogen,lower alkyl or/and azido.

Most preferred alkyl groups are hydroxymethyl, propyl, butyl,2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl,2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to C₁ to C₇ saturated straight, branched or cyclic hydrocarbon.Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl,tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl,optionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferably, lower alkyl is methyl.

The term “alkenyl”, as used herein, is defined as including bothbranched and unbranched, unsaturated hydrocarbon radicals having atleast one double bond, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro,cyano, aryl and heterocycle.

Preferred alkenyl groups are C2-C12 alkenyls, especially C2-6 alkenyls,such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl,1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl,4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl,2-hexenyl and the like, optionally being substituted by one or moresubstituents selected from halogen, cyano, thiocyanato, azido,alkylthio, cycloalkyl, phenyl and acyl. Most preferred is vinyl,optionally substituted by one or more halogen or/and lower alkyl, andespecially 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido,alkylthio, alkyl and acyl.

Preferred alkynyl groups are C2-12 alkynyl, especially C2-6 alkynyl,optionally being substituted by one or more substituents selected fromhalogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl such as phenyland alkyl, preferably cycloalkyl.

Most preferred are ethynyl, propynyl and butynyl, optionally substitutedby lower alkyl or/and halogen, and especially 1-propynyl,cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g. “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of at least onering, most often 1 to 3 rings and generally containing 6-30 carbon atomsby removal of one hydrogen, such as phenyl and naphthyl, each optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonicacid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio,oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl,C1-6-haloalkyl. Aryl radicals are preferably monocyclic or bicycliccontaining 6-10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl each optionally substituted by one or more substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkyl, C1-6-haloalkyl, sulfonyl and phenyl.

Preferred aryl is phenyl, optionally substituted by one or more halogen,lower alkyl, azido or nitro, such as 3-chlorophenyl and 3-azidophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO₂.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “azido”, as used herein, represents a group of the formula —N₃.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO₃H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO₂NH₂.

The term “ester”, as used herein, is defined as including a group offormula —COO—R¹¹ wherein R¹¹ is as defined above except oxy derivative,thio derivative or amino derivative. Preferred are esters of formula—COOR¹¹ wherein R¹¹ is selected from C1-12 alkyl, C2-12 alkenyl, C2-12alkynyl and aryl. Most preferred are esters where R¹¹ is a lower alkyl,especially methyl.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH₂ or—CONHR¹¹ or —CONR¹¹R¹² wherein R¹¹ and R¹² are as defined above.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl, and optionallybeing substituted with any suitable group, including but not limited toone or more moieties selected from lower alkyl, or other groups asdescribed above for the alkyl groups. Non-limiting examples ofheterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl,triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thiomorpholinyl, thieno (2,3-b) furanyl,furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl,thianthrenyl, benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl,quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl,indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholino, morpholinyl, 1-oxaspiro(4.5) dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) optionally substitutedby alkyl or as described above for the alkyl groups. Theterm“heterocycle” also includes bicyclic, tricyclic and tetracyclic,spiro groups in which any of the above heterocyclic rings is fused toone or two rings independently selected from an aryl ring, a cyclohexanering, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring oranother monocyclic heterocyclic ring or where a monocyclic heterocyclicgroup is bridged by an alkylene group, such as quinuclidinyl,7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl,8-azabicyclo(3.2.1)octanyl.

The heterocycle is preferably selected from triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyland piperazinyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino,acyl and phenyl.

More preferably the heterocycle is selected from tetrazolyl,pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, eachoptionally substituted by one or more substituents selected fromhalogen, alkyl, halogen substituted alkyl, acyl, alkoxy, nitro, aminoand phenyl, and especially from 2- and 3-thienyl, optionally substitutedby one or more halogen, acyl such as formyl, cyano and/or lower alkyl,such as methyl.

In the above definitions it is to be understood that when a substituentsuch as R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰ is attached to the rest ofthe molecule via a heteroatom or a carbonyl, a straight- or branchedchain, C1-12-, preferably C1-4-alkylene or C2-12, preferablyC2-4-alkenylene or -alkynylene bridge may optionally be interposedbetween the heteroatom or the carbonyl and the point of attachment tothe rest of the molecule.

The term “R substituent” refers to R¹, R², R³, R⁴ or R⁵, independently.

According to a preferred embodiment, a compound of formula I is asdefined above wherein n represents 0. The compound is a 6-ring structure(2-thioxo- or 2-oxo-piperidinyl derivative) wherein R¹ is not existentsince n=0, and is depicted by the formula (I-A).

According to a following embodiment, the compound of formula I is asdefined above wherein n represents 1. The compound is a 7-ring structure(2-thioxo- or 2-oxo-azepanyl derivative) wherein R¹ is existent sincen=1 and depicted by the formula (I-B).

According to a more preferred embodiment, said compound is as definedabove wherein n=0, R³ and/or R⁴ are different from hydrogen and R² andR⁵ represent hydrogen.

According to another more preferred embodiment, said compound is asdefined above wherein n=1, R², R³ and/or R⁴ are different from hydrogenand wherein R¹ and R⁵ represent hydrogen.

According to a yet more preferred embodiment, said compound is asdefined above wherein only one R substituent chosen from R³ or R⁴ whenn=0 or from R², R³ or R⁴ when n=1, is different from hydrogen and theremaining R substituent(s) is/are hydrogen. We hereby refer to amono-substituted 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo- or2-oxo-azepanyl derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein A¹ represents an oxygen atom. We hereby refer to2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein X is CONR⁷R⁸, especially CONH₂. We hereby refer toamido derivatives of 2-oxo (or thioxo)-piperidinyl or 2-oxo (orthioxo)-azepanyl.

According to another preferred embodiment, compounds of formula I are asdefined above wherein R⁶ represents hydrogen, C1-4 alkyl, or aCH₂—R^(6a) group wherein R^(6a) represents a heterocycle. Mostpreferably R⁶ is a C1-4 alkyl, especially ethyl. When R⁶ is ethyl werefer to 2-(2-oxo (or thioxo)-1-piperidinyl) butanamide or 2-(2-oxo (orthioxo)-1-azepanyl) butanamide derivatives.

According to another preferred embodiment, compounds of formula I are asdefined above wherein the carbon atom to which R⁶ is attached is of theS configuration. In case where R⁶ is ethyl, A is oxygen and X is CONR⁷R⁸we refer then to (2S)-2-(2-oxo-1-piperidinyl) butanamide or(2S)-2-(2-oxo-1-azepanyl) butanamide derivatives.

According to a preferred embodiment, the compound is as defined abovewherein R² when n=1, R³ and R⁴ are the same or different and each isindependently hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amido,sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl,heterocycle, acyl derivative, sulfonyl derivative or sulfinylderivative;

R¹ when existent, R² when n=0 and R⁵ are hydrogen;

R⁶ is hydrogen, alkyl, aryl or —CH₂—R^(6a) wherein R^(6a) is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;

According to this preferred embodiment, the compound is generally suchthat when R⁶ is benzyl, X is —COOCH₃ and n=1, R² is different frommethyl when R³ and R⁴ are both hydrogen and R⁴ is different from methylwhen R² and R³ are both hydrogen.

According to another preferred embodiment, the compound is as definedabove wherein R² when n=1, R³ and R⁴ are the same or different and eachis independently hydrogen; cyano; carboxy; amido;

C1-12 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cycloalkyl, acyl, aryl and heterocycle;

C2-12 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl;

C2-12 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl; acyl derivative of formula —CO—R¹¹, wherein R¹¹ is selectedfrom C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl;

ester of formula —CO—O—R¹¹ wherein R¹¹ is selected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl and aryl;

heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl,each optionally substituted by one or more substituents selected fromhalogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl andphenyl;

aryl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino,azido, sulfonyl, aryl and nitro.

According to another preferred embodiment, the compound is as definedabove, wherein R² when n=1, R³ and R⁴ are the same or different and eachis independently hydrogen;

C1-7 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cyclopropyl, acyl and phenyl;

C2-6 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl;

C2-6 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl; heterocycle selected from tetrazolyl, pyrrolidinyl,pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionallysubstituted by one or more substituents selected from halogen, alkyl,halogen substituted alkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino,azido, sulfonyl, phenyl and nitro.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently C1-4-alkyl or C3-7-cycloalkyl, optionally substituted byone or more halogen, hydroxy, lower alkyl and/or azido.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently vinyl, optionally substituted by one or more halogenor/and lower alkyl.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently ethynyl, propynyl or butynyl, optionally substituted byone or more halogen and/or lower alkyl.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently phenyl, optionally substituted by one or more halogen,lower alkyl, azido and/or nitro.

According to another preferred embodiment, the compound is as definedabove wherein at least one of the R substituents chosen from the groupR², R³ and R⁴ when n=1 or from the group R³ and R⁴ when n=0, representsindependently 2- or 3-thienyl, optionally substituted by one or morehalogen, acyl, cyano or/and lower alkyl.

According to a particular preferred embodiment, the compound is asdefined above wherein at least one of the R substituents chosen from thegroup R³, R⁴ and R² when n=1 or from the group R³ and R⁴ when n=0, ishydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl,2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl,2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl,2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl,5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl,3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl,1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl,2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl,2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to yet another preferred embodiment, the compound is asdefined above wherein R¹, R², R⁴ and R⁵ are hydrogen.

According to even another preferred embodiment, the compound is asdefined above wherein R¹, R², R³ and R⁵ are hydrogen.

According to even another preferred embodiment, the compound is asdefined above wherein n=1 and R′, R³, R⁴ and R⁵ are hydrogen.

In all the above-mentioned scopes when the carbon atom to which R⁶ isattached is asymmetric it is preferably in the“S”-configuration.

Representative compounds useful in the methods and compositions of thisinvention as defined above are selected from the group consisting of

-   2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-propyl-1-piperidinyl)butanamide,-   2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,-   2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,-   2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,-   2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,-   2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,-   2[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,-   2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,-   2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-4-propyl-1-piperidinyl)butanamide,-   2-[2-oxo-4-(3,3,3trifluoropropyl)-1-piperidinyl]butanamide,-   2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,-   2[2-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,-   2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,-   2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,-   2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,-   2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,-   2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,-   2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,-   2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-5-propyl-1-azepanyl)butanamide,-   2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-5-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,-   2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,-   2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-6-propyl-1-azepanyl)butanamide,-   2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-6-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,-   2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,-   2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-4-propyl-1-azepanyl)butanamide,-   2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,-   2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,-   2-(2-oxo-4-phenyl-1-azepanyl)butanamide,-   2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,-   2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,-   2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,-   2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,-   2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,-   2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,-   2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,-   2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,-   2-[4-(2,2,2-tritluoroethyl)-2-oxo-1-azepanyl]butanamide.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:

-   (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,-   (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

iii) International Patent Application WO 2004/087658:

A compound having the formula I or a pharmaceutically acceptable saltthereof or stereoisomeric forms thereof,

wherein

R¹ is hydrogen,

R² is hydrogen or C1-20-alkyl,

R³ is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl,aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group offormula —W—R⁸, R^(3a) is hydrogen, C1-20-alkyl or a group of formula:

or NR³R^(3a) is a group of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; azido; cyano; —S—C1-4-alkyl;—SO—C1-4-alkyl; —SO₂—C1-4-alkyl; —SONH₂; C1-20-alkyl unsubstituted orsubstituted by halogen; or C1-20-alkoxy unsubstituted or substituted byhalogen,

R⁶ is hydrogen, C1-20-alkyl or halogen,

R⁷ is hydrogen, C1-20-alkyl or halogen,

W is C1-12-alkylene, —NH— or —NHC(═O)—,

-   -   X is O, S or NH,    -   Y is O, S, —CR¹²R¹³—, —NR¹⁴— or —C(═O)—,

R⁸ is aryl or heterocycle,

R⁹, R¹⁰, R^(10a) and R¹¹ are independently selected from hydrogen,C1-4-alkyl, halogen, hydroxy or methoxycarbonyl,

or R¹⁰ and R^(10a) together form a C3-6-alkylene,

R¹² is hydrogen, C1-4-alkyl, halogen or hydroxy,

R¹³ is hydrogen,

or CR¹²R¹³ is dioxolanyl,

R¹⁴ is aryl, heterocycle or a group of formula —V—R¹⁵,

V is C₁₋₁₂-alkylene,

R¹⁵ is aryl or heterocycle,

m is 1 to 4,

n is 0 or 1,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

In another aspect, the compound has the formula I or a pharmaceuticallyacceptable salt thereof or stereoisomeric forms thereof,

wherein

R¹ is hydrogen,

R² is hydrogen or C1-20-alkyl,

R³ is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl,aromatic or non aromatic heterocycle, C1-20-alkoxy, or a group offormula —W—R⁸,

R^(3a) is hydrogen, C1-20-alkyl or a group of formula:

or NR³R^(3a) is a group of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; C1-20-alkyl unsubstituted or substitutedby halogen; or C1-20-alkoxy unsubstituted or substituted by halogen,

R⁶ is hydrogen, C1-20-alkyl or halogen,

R⁷ is hydrogen, C1-20-alkyl or halogen,

W is C1-12-alkylene, —NH— or —NHC(═O)—,

X is O, S or NH,

Y is O, S, —CR¹²R¹³—, —NR¹⁴— or —C(═O)—,

R⁸ is aryl or heterocycle,

R⁹, R¹⁰, R^(10a) and R¹¹ are independently selected from hydrogen,C1-4-alkyl, halogen, hydroxy or methoxycarbonyl,

or R¹⁰ and R^(10a) together form a C3-6-alkylene,

R¹² is hydrogen, C1-4-alkyl, halogen or hydroxy,

R¹³ is hydrogen,

or CR¹²R¹³ is dioxolanyl,

R¹⁴ is aryl, heterocycle or a group of formula —V—R¹⁵,

V is C1-12-alkylene,

R¹⁵ is aryl or heterocycle,

m is 1 to 4,

n is 0 or 1,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and containing 1-20 carbon atoms,preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms fornon-cyclic alkyl and 3-8 carbon atoms for cycloalkyl. Alliyl moietiesmay optionally be substituted by 1 to 5 substituents independentlyselected from halogen, hydroxy, alkoxy, alkoxycarbonyl, ester oralkylamino. Preferred alkyl groups are methyl, ethyl, n-propyl,isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl,3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl) propyl,3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and3-(dimethylamino) propyl.

The term “cycloalkyl”, as used herein, refers to a monovalent group of 3to 18 carbon atoms, preferably 4-8 carbon atoms, derived from asaturated cyclic or polycyclic hydrocarbon which may be substituted byany suitable group including but not limited to one or more moietiesselected from groups as described above for the alkyl groups. Preferredcycloalkyl group is cycloheptyl.

The term “alkylene”, as used herein, represents a divalent alkyl group,having straight or branched moieties, containing 1-12 carbon atoms,preferably 1-6 carbon atoms, and being optionally substituted with anysuitable group, including but not limited to one or more moietiesselected from groups as described above for the alkyl groups. Preferredalkylene groups are methylene, ethylene, hydroxyethylene, trimethyleneor propylene.

The term “cycloalkenyl”, as used herein, is defined as a cyclicunsaturated hydrocarbon radical having at least one double bond,containing 4-20 carbon atoms, preferably 5-8 carbon atoms, and beingoptionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferred cycloalkenyl group is6-(hydroxymethyl)cyclohex-3-en-1-yl.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of 1-3 rings andcontaining 6-30 carbon atoms by removal of one hydrogen, such as phenyland naphthyl each optionally substituted by 1 to 5 substituentsindependently selected from halogen, hydroxy, nitro, C1-6-alkyl,C1-6-alkoxy, C1-6-alkylsulfonyl, trifluoromethylthio or pyridinylalkyl.Aryl radicals are preferably phenyl radicals. Preferred aryl groups arephenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl,4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl,3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl,4-methylsulfonylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl,2-[(trifluoromethyl)thio]phenyl, 2-chlorophenyl or 4-bromophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “nitro”, as used herein, represents a group of the formula—NO₂.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(b)wherein R^(b) is an alkyl group, as defined above.

The term “ester”, as used herein, represents a group of formula—COOR^(C) wherein R^(c) is an alkyl group or an aryl group, as definedabove.

The term “alkoxycarbonyl”, as used herein, represents a group of formula—COOR^(d) wherein R^(d) is an alkyl group, as defined above.

The term “amino”, as used herein, represents a group of the formula—NH₂.

The term “alkylamino”, as used herein, represents a group of formula—NHR^(e) or —NR^(e)R^(f) wherein R^(e) and R^(f) are alkyl group asdefined above.

The term alkylsulfonyl, as used herein is defined as representing agroup of formula —SO₂—R^(g), wherein R^(g) is C1-4-alkyl.

The term “heterocycle”, as used herein is defined as including anaromatic or non aromatic cycloalkyl or cycloalkenyl moiety as definedabove, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl.

Non-limiting examples of aromatic heterocycles are pyrazolyl, furyl,imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl,isothiazolyl, benzimidazolyl, tetrazolyl, isooxazolyl, oxazolyl,thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl,pyrazinyl, isoindolyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolizinyl,naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl,indolyl, indolizinyl, purinyl, carbazolyl, thieno (2,3-b) furanyl,thianthrenyl, benzothiazolyl, benzoxazolyl, cinnolinyl, quinoxalinyl,phenothiazinyl, isochromanyl and xanthenyl, optionally substituted by 1to 5 substituents independently selected from halogen, hydroxy, thiol,amino, nitro, cyano, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl,C1-6-haloalkyl, formyl or ester. More preferred aromatic heterocyclesare pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl and pyridinyl.

Non-limiting examples of non aromatic heterocycles aretetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl,tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl,oxooctahydroquinolinyl, dioxolanyl, 1-oxaspiro(4.5) dec-2-yl,pyrrolidinyl, 2-oxo-pyrrolidinyl, 8-thiabicyclo[3.2.1]cyclooctanyl,1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl,optionally substituted by 1 to 5 substituents independently selectedfrom halogen, hydroxy, thiol, amino, nitro, cyano, azido, C1-6-alkoxy,C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl, formyl or ester. Morepreferred non aromatic heterocycles are tetrahydrofuranyl, piperidinyl,piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazocin-1(2H)-yl, 3,4-dihydro-1H-isochromen-1-yl, tetrahydropyranyl,oxooctahydroquinolinyl and dioxolanyl. The term“heterocycle” alsoincludes bicyclic, tricyclic and tetracyclic, spiro groups in which anyof the above heterocyclic rings is fused to one or two ringsindependently selected from an aryl ring, a cycloalkyl ring, acycloalkenyl ring or another monocyclic heterocyclic ring or where amonocyclic heterocyclic group is bridged by an alkylene group, such asquinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyland 8-azabicyclo(3.2.1)octanyl.

The term “pyridinylalkyl”, as used herein, represents a group of formula—R^(h)-pyridinyl in which R^(h) is C1-4-alkylene.

The term “azido” as used herein, represents a group of the formula —N₃.

The term “cyano” as used herein, represents a group of the formula —CN.

Generally, R² is hydrogen or C1-4-alkyl.

Preferably, R² is hydrogen, methyl or ethyl. More preferably, R² ishydrogen or methyl.

Generally, R³ is hydrogen; C1-6-alkyl unsubstituted or substituted by 1to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonylor alkylamino; C5-7-cycloalkyl; (hydroxymethyl) cyclohexenyl; phenylunsubstituted or substituted by 1 to 5 substituents selected fromhalogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl,trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted orsubstituted by methoxy; triazolyl; C1-4-alkoxy; or a group of formula—W—R⁸ wherein:

Generally, W is C1-4-alkylene unsubstituted or substituted by halogen,hydroxy, C1-4-alkyl or alkoxy; —NH—; or —NHC(═O)—; and

R⁸ is phenyl unsubstituted or substituted by 1 to 5 substituentsselected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro,methylsulfonyl or trifluoromethylthio; furyl unsubstituted orsubstituted by methyl; pyrazolyl; pyridinyl; morpholinyl;tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted bymethyl; dihydroisochromenyl or dihydroimidazolyl.

Preferably, R³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl,3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl) propyl,3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl,3-(dimethylamino) propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl,3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl,3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl,4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl,2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl,2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino,pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl,pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl,2-morpholin-4-ylethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl, 2-(2-methylpiperidin-1-yl)ethyl,3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy,(4-pyridinylcarbonyl)amino or 4,5-dihydro-1H-imidazol-2-ylamino. Morepreferably, R³ is hydrogen.

Generally, R^(3a) is hydrogen, C1-4-alkyl or a group of formula

wherein m is 1 to 4.

Preferably, R^(3a) is hydrogen, methyl or tetrahydrofuran-2-ylmethyl.More preferably, R^(3a) is hydrogen.

In another embodiment, NR³R^(3a) is piperidinyl unsubstituted orsubstituted by hydroxy; thiomorpholinyl; thiazolidinyl unsubstituted orsubstituted by C1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl;1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or agroup of formula

wherein R¹⁴ is pyridinyl; phenyl unsubstituted or substituted byhalogen, hydroxy, C1-4-alkyl; or a group of formula —V—R¹⁵ wherein V isunsubstituted C1-4-alkylene and R¹⁵ is phenyl or morpholinyl.

In a preferred embodiment, NR³R^(3a) is 4-pyridin-2-ylpiperazin-1-yl,4-(3-methylphenyl) piperazin-1-yl, 4-(4-hydroxyphenyl) piperazin-1-yl,4-(2-phenylethyl) piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl,4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl,1,4-dioxa-8-azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl.

Generally, R⁵ is hydrogen, nitro, halogen, C1-4-alkyl, unsubstituted orsubstituted by halogen, or C1-4-alkoxy unsubstituted or substituted byhalogen.

Preferably, R⁵ is hydrogen, methyl, ethyl, trifluoromethyl,trifluoromethoxy, n-propyl, isopropyl, nitro, or halogen. Morepreferably, R⁵ is halogen or trifluoromethyl.

Generally, R⁶ is hydrogen, C1-6-alkyl or halogen.

Preferably, R⁶ is hydrogen, methyl or Cl. More preferably, R⁶ ishydrogen.

Generally, R⁷ is hydrogen, methyl or halogen.

Preferably, R⁷ is hydrogen, methyl, Br, F or Cl. More preferably, R⁷ ishydrogen, Br or F.

Combinations of one or more of these preferred compound groups areespecially preferred.

In a preferred embodiment, the compound has the formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof,

wherein R¹ is hydrogen,

R² is hydrogen or C1-4-alkyl,

R³ is hydrogen; C1-6-alkyl unsubstituted or substituted by 1 to 5substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl oralkylamino; C5-7-cycloalkyl; (hydroxymethyl) cyclohexenyl; phenylunsubstituted or substituted by 1 to 5 substituents selected fromhalogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl,trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted orsubstituted by methoxy; triazolyl; C1-4-alkoxy; or a group of formula—W—R⁸,

R^(3a) is hydrogen, C1-4-alkyl or a group of formula

or NR³R^(3a) is piperidinyl unsubstituted or substituted by hydroxy;thiomorpholinyl; thiazolidinyl unsubstituted or substituted byC1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl;1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or agroup of formula

R⁴ is hydrogen,

R⁵ is hydrogen; nitro; halogen; C1-4-alkyl, unsubstituted or substitutedby halogen; or C1-4-alkoxy unsubstituted or substituted by halogen,

R6 is hydrogen, C1-6-allyl or halogen,

R7 is hydrogen, methyl or halogen, W is C1-4-alkylene unsubstituted orsubstituted by halogen, hydroxy, C1-4-alkyl or alkoxy; —NH—; or—NHC(═O)—,

R8 is phenyl unsubstituted or substituted by 1 to 5 substituentsselected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro,methylsulfonyl or trifluoromethylthio; furyl unsubstituted orsubstituted by methyl; pyrazolyl; pyridinyl; morpholinyl;tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted bymethyl; dihydroisochromenyl or dihydroimidazolyl,

R¹⁴ is pyridinyl; phenyl unsubstituted or substituted by halogen,hydroxy, C1-4-alkyl; or a group of formula —V—R¹⁵,

V is unsubstituted C1-4-alkylene,

R¹⁵ is phenyl or morpholinyl,

m is 1 to 4,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

In a more preferred embodiment, the compound has the formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof,

wherein

R¹ is hydrogen,

R² is hydrogen, methyl or ethyl,

R³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl,3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl) propyl,3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl,3-(dimethylamino) propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl,3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl,3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl,4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl,2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl,2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino,pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl,pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl, 2-morpholin-4-ylethyl,2-((3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl,2-(2-methylpiperidin-1-yl)ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl,methoxy, (4-pyridinylcarbonyl)amino or4,5-dihydro-1H-imidazol-2-ylamino,

R^(3a) is hydrogen, methyl or tetrahydrofuran-2-ylmethyl, or NR³R^(3a)4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl) piperazin-1-yl,4-(4-hydroxyphenyl)piperazin-1-yl, 4-(2-phenylethyl)piperazin-1-yl,4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl,thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3-yl,2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or4-oxooctahydro-1(2H)-quinolinyl,

R⁴ is hydrogen,

R5 is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy,n-propyl, isopropyl, nitro or halogen,

R⁶ is hydrogen, methyl or Cl,

R⁷ is hydrogen, methyl, Br, F or Cl,

and at least one of R⁵, R⁶ or R⁷ is different from hydrogen when R² ishydrogen, R³ is H or 2,6-diisopropylphenyl, and R^(3a) is H.

More preferably, R² is hydrogen or methyl, R³ is hydrogen, R^(3a) ishydrogen, R⁵ is halogen or trifluoromethyl, R⁶ is hydrogen and R⁷ ishydrogen, Br or F.

In all the above-mentioned scopes, when R² is C1-20-alkyl, the carbonatom to which R² is attached is preferably in the“S”-configuration.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) propanamide;(2R)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;2-[2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-1-yl]acetamide;2-(5-isopropyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(2-oxo-5-propyl-2,3-dihydro-1H-indol-1-yl) acetamide;2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide;2-(5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(7-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide;(+)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide;(−)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide;2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;(+)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;(−)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;(−)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;(+)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorophenyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenyllacetarnide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetanuide;5-chloro-1-[2-oxo-2-(4-pyridin-2-ylpiperazin-1-yl)ethyl3-1,3-dihydro-2H-indol-2-one;5-chloro-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)acetamide;5-chloro-1-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N′-isonicotinoylacetohydrazide;5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1,2,4-triazol-3-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[4-(methylsulfonyl)benzyl]acetamide;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]octahydroquinolin-4(1H)-one;N′-(4-bromophenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetohydrazide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(6-methoxypyridin-3-yl)acetamide;N-butyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl]acetamide;5-chloro-1-{2-oxo-2-[4-(2-phenylethyl)pperazin-1-yl]ethyl}-1,3-dihydro-2H-indol-2-one;ethyl {[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetyl]amino}acetate;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-fluoroethyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dimethylphenyl)acetamide;N-(4-tert-butylphenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[1-(hydroxymethyl)propyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-hydroxy-2-phenylethyl)acetamide;5-chloro-1-{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl]acetamide;methyl3-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl]acetyl]-1,3-thiazolidine-4-carboxylate;5-chloro-1-[2-(2,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N′-(4,5-dihydro-1H-imidazol-2-yl)acetohydrazide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-chlorophenyl)etl-lyllacetaniide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-morpholin-4-ylethyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-methylpiperidin-1-yl)ethyl]acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-nitrobenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dihydro-1H-isochromen-1-ylinethyl)acetamide;N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-{2-[(trifluoromethyl)thio]benzyl}acetamide;5-chloro-1-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-cycloheptylacetamide;5-chloro-1-{2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; and2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamide.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide;2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide;(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide;2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide and2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide.

In another embodiment, compounds useful in the methods and compositionsof this invention are selected from the group consisting of:2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) acetamide and(2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide.

iv) U.S. Pat. No. 7,244,747:

A compound having the formula I or a pharmaceutically acceptable saltthereof,

wherein R¹ is hydrogen, C₁₋₂₀ alkyl, C₃₋₈ cycloalkyl, halogen, hydroxy,alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, aminoderivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,alkylsulfinyl, arylsulfinyl, aryl or heterocycle;

R² is hydrogen, C₁₋₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;

R³ is hydrogen, C₁₋₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁴ is hydrogen, C₁₋₂₀ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, aryl, azido,alkoxycarbonylamino, arylsulfonyloxy or heterocycle;

R^(4a) is hydrogen or C₁₋₂₀ alkyl;

or R⁴ and R^(4a) can form together a C₃₋₈ cycloalkyl;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R⁶ is hydrogen or C₁₋₂₀ alkyl;

R⁷ is hydrogen;

or R⁶ and R⁷ are linked together to form a C₃₋₆ cycloalkyl;

R⁸ is hydrogen, halogen, nitro, cyano, C₁₋₂₀ alkyl or alkoxy;

R⁹ is hydrogen, C₁₋₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R¹⁰ is hydrogen, C₁₋₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R¹¹ is hydrogen, halogen, nitro, cyano, C₁₋₂₀ alkyl or alkoxy;

R¹² is hydrogen or halogen;

R¹³ is hydrogen, nitro, halogen, heterocycle, amino, aryl, C₁₋₂₀ alkylunsubstituted or substituted by halogen, or alkoxy unsubstituted orsubstituted by halogen;

R¹⁴ is hydrogen, C₁₋₂₀ alkyl or halogen;

R¹⁵ is hydrogen, C₁₋₂₀ alkyl or halogen;

with the proviso that R⁴ is different from hydrogen when represents agroup of formula

The asterisk * indicates the point of attachment of the substituents.

In a preferred embodiment, the compounds have the formula I, theirtautomers, geometrical isomers (including cis and trans, Z and Eisomers), enantiomers, diastereoisomers and mixtures thereof (includingall possible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein R¹ is hydrogen, C₁₋₂₀ alkyl, C₃₋₈ cycloalkyl, halogen, hydroxy,ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl,alkylsulfinyl, aryl or heterocycle;

R² is hydrogen, C₁₋₂₀ alkyl, halogen, cyano, ester, carbamate or amido;

R³ is hydrogen, cyano, C₁₋₂₀ alkyl, halogen or ester;

-   -   or R² and R³ can form together with the imidazole ring the        following 1H-benzimidazole cycle

R⁴ is hydrogen, C₁₋₂₀ alkyl, C₂₋₁₂ alkenyl or aryl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R⁶ is hydrogen or C₁₋₂₀ alkyl;

R⁷ is hydrogen; or R⁶ and R⁷ are linked together to form a C₃₋₆cycloalkyl;

R⁸ is hydrogen;

R⁹ is hydrogen, C₁₋₂₀ alkyl, halogen or alkoxy;

R¹⁰ is hydrogen, C₁₋₂₀ alkyl, halogen or cyano;

R¹¹ is hydrogen;

R¹² is hydrogen or halogen;

R¹³ is hydrogen, halogen, heterocycle or C₁₋₂₀ alkyl;

R¹⁴ is hydrogen;

R¹⁵ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

The term “alkyl”, as used herein, represents saturated, monovalenthydrocarbon radicals having straight (unbranched) or branched or cyclicor combinations thereof and containing 1-20 carbon atoms, preferably1-10 carbon atoms, more pre preferred alkyl groups have 1-3 carbonatoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhalogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkythio,alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl or aryl. Usually alkyl groups, in the presentcase, are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl,trifluoromethyl, 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl,(acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl,(4-chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio)ethyl.Preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl,azidomethyl, (acetylamino)methyl, (propionylamino)methyl,(benzoylamino)methyl or 2-(methylthio)ethyl. More preferred alkyl groupsare methyl, ethyl, n-propyl, i-propyl, n-butyl, azidomethyl ortrifluoromethyl. Most preferred alkyl groups are methyl or n-propyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturatedcyclic hydrocarbon, which may be substituted by any suitable groupincluding but not limited to one or more moieties selected from groupsas described above for the alkyl groups. Preferred cycloalkyl groups arecyclopropyl and cyclohexyl.

The term “alkenyl” as used herein, represents straight, branched orcyclic unsaturated hydrocarbon radicals or combinations thereof havingat least one carbon-carbon double bond, containing 2-12 carbon atoms,preferably usually 2-4 carbon atoms. Alkenyl groups are being optionallysubstituted with any suitable group, including but not limited to one ormore moieties selected from groups as described above for the alkylgroups. Usually an alkenyl group is ethenyl (vinyl) optionallysubstituted by 1 to 3 halogens. Preferred alkenyl group, in the presentcase, is 2,2-difluorovinyl.

The term a “alkynyl” as used herein, represents straight, branched orcyclic hydrocarbon radicals or combinations thereof containing at leastone carbon-carbon triple bond, containing 2-12 carbon atoms, preferably2-6 carbon atoms, and being optionally substituted by any suitablegroup, including but not limited to one or more moieties selected fromgroups as described above for the alkyl groups. Preferably an alkynylgroup is a halogenoalkynyl group (haloalkynyl group).

Groups qualified by prefixes such as “s”, “i”, “t” and the like (e.g.“i-propyl”, “s-butyl”) are branched derivatives.

The term “aryl” as used herein, is defined as phenyl optionallysubstituted by 1 to 4 substituents independently selected from halogen,cyano, alkoxy, alkylthio, C₁₋₃ alkyl or azido, preferably halogen orazido. Usually aryl groups, in the present case are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or3-azido-2,4,6-trifluorophenyl. Preferably, aryl groups are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferred arylgroups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cycloalkyl moiety as defined above, having atleast one O, S and/or N atom interrupting the carbocyclic ringstructure. Heterocyclic ring moieties can be optionally substituted byalkyl groups or halogens and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Usuallyheterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl,1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl,4-chloro-1-methyl-1H-pyrazol-3-yl,5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl,3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl,4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. Preferredheterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl,1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2-yl,1H-pyrrol-2-yl.

The term “halogen”, as used herein, includes an atom of chlorine,bromine, fluorine, iodine. Usually halogens are chlorine, bromine andfluorine. Preferred halogens are fluorine, bromine and chlorine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(a)

wherein R^(a) is an alkyl group, as defined above. Preferred alkoxygroup is methoxy.

The term “aryloxy”, as used herein, represents a group of formula—OR^(b) wherein R^(b) is an aryl group, as defined above. Preferredaryloxy group is phenoxy.

The term “ester”, as used herein, represents a group of formula—COOR^(c) wherein R^(c) is an alkyl group or aryl group, as definedabove. Preferred ester group is methoxycarbonyl.

The term “amido”, as used herein, represents a group of formula —CONH₂.

The term “amino”, as used herein, represents a group of formula —NH₂.

The term “aminoderivative”, as used herein, represents an alkylamino oran arylamino group, wherein the terms “alkyl” and “aryl” are defined asabove.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “nitro”, as used herein, represents a group of formula —NO₂.

The term “azido”, as used herein, represents a group of formula —N₃.

The term “guanidine”, as used herein, represents a group of formula—NHC(═NH)NH₂.

The term “alkylthio”, as used herein, represents a group of formula—SR^(d) wherein R^(d) is an alkyl group, as defined above. Preferredalkylthio group is methylthio.

The term “alkylsulfonyl”, as used herein, represents a group of formula—S(═O)₂R^(e) wherein R^(e) is an alkyl group, as defined above.Preferred alkylsulfonyl group is methylsulfonyl.

The term “alkylsulfinyl”, as used herein, represents a group of formula—S(═O)R^(f) wherein R^(f) is an alkyl group, as defined above. Preferredalkylsulfinyl group is methylsulfinyl.

The term “arylthio”, as used herein, represents a group of formula—SR^(g) wherein R^(g) is an aryl group, as defined above.

The term “arylsulfonyl”, as used herein, represents a group of theformula —S(═O)₂R^(h) wherein R^(h) is an aryl group, as defined above.

The term “arylsulfinyl”, as used herein, represents a group of theformula —S(═O)R^(i) wherein R^(i) is an aryl group, as defined above.

The term “carbamate” as used herein, represents a group of formula—N(H)C(O)OR^(j), wherein R^(j) is an alkyl or an aryl, as defined above.Usually carbamate groups are (propoxycarbonyl)amino or(benzyloaxycarbonyl)amino. Preferred carbamate group is(benzyloaxycarbonyl)amino.

The term “alkanoylamino” as used herein, represents a group of theformula —NHC(═O)R^(k) wherein R^(k) is an alkyl group, as defined above.

The term “(arylcarbonyl)amino” as used herein, represents a group of theformula —NHC(═O)R^(m) wherein R^(m) is an aryl group, as defined above.Preferred (arylcarbonyl)amino is benzoylamino.

Usually, R¹ is hydrogen; C₁₋₁₀ alkyl unsubstituted or substituted byhalogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy;C₃₋₆ cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl groups; or guanidine. Preferably, R¹ is hydrogen;methyl; ethyl; i-propyl; n-propyl; cyclopropyl; n-butyl; i-butyl;t-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl;chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl;2-(methylthio)ethyl; chloro; bromo; nitro; cyano; amino; aminocarbonyl;methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl;2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl;1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. Morepreferably, R¹ is hydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl;methylthio; nitro; cyano; amino; chloro or 1H-pyrrol-2-yl. Mostpreferably, R¹ is hydrogen; methyl; methylthio; nitro; cyano; amino orchloro.

Usually, R² is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably, R² ishydrogen; methyl; hydroxymethyl; (acetylamino)methyl;(propionylamino)methyl; (benzoylamino)methyl;[(benzyloxy)carbonyl]amino; chloro or cyano. More preferably, R² ishydrogen; chloro or cyano.

Usually, R³ is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano. Preferably, R³ is hydrogen;hydroxymethyl; chloro; cyano. More preferably, R³ is hydrogen or cyano.Most preferred R³ is hydrogen.

Usually, R⁴ is hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhalogens; C₂₋₄ alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens. Preferably, R⁴ ishydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl;3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Morepreferably, R⁴ is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R⁴is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or3-azido-2,4-difluorophenyl.

Usually, R^(4a) is hydrogen.

Usually, R⁵ is hydrogen.

Usually, R⁶ is hydrogen or C₁₋₁₀ alkyl unsubstituted or substituted byhydroxy or azido. Preferably, R⁶ is hydrogen or azidomethyl. Morepreferably R⁶ is hydrogen.

Usually R⁷ is hydrogen.

In other preferred embodiments, R⁶ and R⁷ are linked to form acyclopropyl.

In other preferred embodiments, R² and R³ can form together with theimidazole ring the following 1H-benzimidazole cycle

Usually, R⁸ is hydrogen.

Usually, R⁹ is hydrogen; halogen; C₁₋₃ alkyl or alkoxy. Preferably, R⁹is hydrogen; methyl; chloro or methoxy. More preferred R⁹ is hydrogen.

Usually, R¹⁰ is hydrogen; halogen; cyano; C₁₋₃ alkyl unsubstituted orsubstituted by halogens; or alkoxy. Preferably, R¹⁰ is methyl; hydrogen;trifluoromethyl; fluoro; cyano or methoxy. More preferred R¹⁰ ishydrogen; trifluoromethyl; fluoro or cyano.

Usually, R¹¹ is hydrogen.

In other preferred embodiments, R⁴, R^(4a) and R⁵ can form together withthe 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-onecycle

Usually, R¹² is hydrogen or halogen. Preferably R¹² is hydrogen; chloroor fluoro. More preferred R¹² is hydrogen.

Usually, R¹³ is hydrogen; C₁₋₃ alkyl; halogen or thiazolyl unsubstitutedor substituted by alkyl groups, such as methylthiazolyl. Preferably R¹³is hydrogen; chloro; bromo or methyl. Most preferred R¹³ is chloro;bromo or methyl.

Usually R¹⁴ is hydrogen.

Usually, R¹⁵ is hydrogen.

Combinations of one or more of these preferred compound groups areespecially preferred.

Generally, among the embodiments, the compounds of formula I, orpharmaceutically acceptable salts thereof, are those wherein

R¹ is selected from hydrogen; C₁₋₁₀ alkyl unsubstituted or substitutedby halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C₃₋₆cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl group; or guanidine;

R² is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate or [(N-methoxy-N-methyl)amino]carbonyl.

R³ is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano;

R⁴ is selected from hydrogen; C₁₋₄ alkyl unsubstituted or substituted byhalogens; C₂₋₄ alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens;

R^(4a) is hydrogen;

R⁵ is hydrogen;

R⁶ is selected from hydrogen or C₁₋₁₀ alkyl unsubstituted or substitutedby hydroxy or azido;

R⁷ is hydrogen;

or R⁶ and R⁷ can be linked to form a cyclopropyl;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is selected from hydrogen; halogen; C₁₋₃ alkyl; alkoxy;

R¹⁰ is selected from hydrogen; halogen; cyano or C₁₋₃ alkylunsubstituted or substituted by halogens; or alkoxy;

R¹¹ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is selected from hydrogen or halogen;

R¹³ is selected from hydrogen; C₁₋₃ alkyl; halogen; thiazolylunsubstituted or substituted by alkyl groups, such as methylthiazolyl;

R¹⁴ is hydrogen;

R¹⁵ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl;2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl;hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chloro;bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl;1,2,3-thiadiazol-4-yl; or 1H-imidazol-2-yl;

R² is selected from hydrogen; methyl; hydroxymethyl;(acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl;(benzyloxycarbonyl)amino; chloro; or cyano;

R³ is selected from hydrogen; hydroxymethyl; chloro; cyano;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is selected from hydrogen; methyl; choro; methoxy;

R¹⁰ is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano;or methoxy;

R¹¹ is hydrogen;

R⁴ is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl; or3-azido-2,4,6-trifluorophenyl.

R^(4a) is hydrogen; R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is selected from hydrogen; chloro; fluoro;

R¹³ is selected from hydrogen; chloro; bromo; methyl;

R¹⁴ is hydrogen;

R¹⁵ hydrogen;

R⁶ is selected from hydrogen; azidomethyl;

R⁷ is hydrogen;

or R⁶ and R⁷ are linked to form a cyclopropyl;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a more preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;n-butyl; methylthio; nitro; cyano; amino; chloro; or 1H-pyrrol-2-yl;

R² is selected from hydrogen; chloro; cyano;

R³ is selected from hydrogen; cyano;

or R² and R³ can form together with the imidazole ring the following1H-benzimidazole cycle

R⁸ is hydrogen;

R⁹ is hydrogen;

R¹⁰ is selected from hydrogen; trifluoromethyl; fluoro; cyano;

R¹¹ is hydrogen;

R⁴ is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl; or 3-azido-2,4-difluorophenyl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

wherein

R¹² is hydrogen;

R¹³ is selected from methyl; chloro; bromo;

R¹⁴ is hydrogen;

R¹⁵ hydrogen;

R⁶ is hydrogen;

R⁷ is hydrogen;

with the proviso that R⁴ is different from hydrogen when

represents a group of formula

In a most preferred embodiment, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

R¹ is selected from hydrogen; methyl; methylthio; nitro; cyano; amino;chloro;

R² is selected from hydrogen; chloro; cyano;

R³ is hydrogen;

R⁴ is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl;

R^(4a) is hydrogen;

R⁵ is hydrogen;

or R⁴, R^(4a) and R⁵ can form together with the 2-oxo-1-pyrrolidine ringthe following 1,3-dihydro-2H-indol-2-one cycle

R¹² is hydrogen;

R¹³ is selected from chloro; bromo; methyl;

R¹⁴ is hydrogen;

R¹⁵ hydrogen;

R⁶ is hydrogen;

R⁷ is hydrogen.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide,4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;methyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxyla-te;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,4-dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(5-methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(4-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;benzyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-5-ylcarbamat-e;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide;1-(1H-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-on-e;{1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetoni-trile;1-[(5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one-;1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;1-[(6-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-car-bonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-pro-pylpyrrolidin-2-one;1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile;1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylp-yrrolidin-2-one;1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl-)-1H-benzimidazole-5-carbonitrile;1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrr-olidin-2-one;1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl-}pyrrolidin-2-one;1-{[2-(3-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propyl-pyrrolidin-2-one;1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-methyl}pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile;and1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-c-arbonitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one,1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(11H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+);1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-car-bonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbo-nitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-on-e;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbo-nitrile.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of:(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

v) International Patent Application WO 2007/065595:

Compounds having formula I, their enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers), orpharmaceutically acceptable salts thereof,

wherein

R¹ is hydrogen or C₁₋₆ alkyl;

R² is hydrogen or C₁₋₄ alkyl;

R³ is a group of formula —CHR⁵R⁶ or a benzyl group;

R⁴ is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl, C3-6cycloalkyl, aryl or heterocycle;

R⁵ is C2-4 alkyl;

R⁶ is C2-4 alkyl, amido or —COOR⁷;

R⁷ is C1-4 alkyl;

Usually when R³ is a benzyl group, then R⁴ is C₁₋₈ alkyl optionallysubstituted by alkoxycarbonyl.

Usually when R³ is a group of formula —CHR⁵R⁶ then R⁴ is C₁₋₈ alkyloptionally substituted by C₃₋₆ cycloalkyl, aryl or heterocycle.

The term “alkyl”, as used herein, is a group which represents saturated,monovalent hydrocarbon radicals having straight (unbranched) or branchedmoieties, or combinations thereof, and containing 1-8 carbon atoms,preferably 1-6 carbon atoms; more preferably alkyl groups have 1-4carbon atoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl orheterocycle. Alkyl moieties may be optionally substituted by acycloalkyl as defined hereafter. Preferred alkyl groups are methyl,cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl,2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, i-butyl, n-pentyl,3-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl,(3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. Morepreferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl,n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl,benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl,(3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. Mostpreferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzylor (5-nitro-2-furyl)methyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclichydrocarbon, which may be substituted by any suitable group includingbut not limited to one or more moieties selected from groups asdescribed above for the alkyl groups. Preferred cycloalkyl group iscyclohexyl.

The term “aryl” as used herein, is defined as a phenyl group optionallysubstituted by 1 to 4 substituents independently selected from halogen,amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl,3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term “phenyl”, as used herein, represents an aromatic hydrocarbongroup of formula —C₆H₅.

The term “benzyl group”, as used herein, represents a group of formula—CH₂-aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groupsare benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or3-aminobenzyl. Most preferred alkyl groups are 3-methoxybenzyl or3-nitrobenzyl.

The term “halogen”, as used herein, represents an atom of fluorine,chlorine, bromine, or iodine. Preferred halogen is bromine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “amino”, as used herein, represents a group of formula —NH₂.

The term “ethynyl”, as used herein, represents a group of formula —C≡CH.

The term “alkoxy”, as used herein, represents a group of formula —OR^(a)wherein R^(a) is an alkyl group, as defined above. Preferred alkoxygroup is methoxy.

The term “nitro”, as used herein, represents a group of formula —NO₂.

The term “amido”, as used herein, represents a group of formula—C(═O)NH2.

The term “acyl”, as used herein, represents a group of formula—C(═O)R^(b) wherein R^(b) is an alkyl group, as defined here above.Preferred acyl group is acetyl (—C(═O)Me).

The term “alkoxycarbonyl (or ester)”, as used herein, represents a groupof formula —COOR^(c) wherein R^(c) is an alkyl group; with the provisothat R^(c) does not represent an alkyl alpha-substituted by hydroxy.Preferred alkoxycarbonyl group is ethoxycarbonyl.

The term “heterocycle”, as used herein, represents a 5-membered ringcontaining one or two heteroatoms selected from O or N. The heterocyclemay be substituted by one or two C₁₋₄ alkyl or nitro. Preferredheterocycles are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). Mostpreferred heterocycle is (5-nitro-2-furyl).

Generally R¹ is hydrogen or C₁₋₆ alkyl. Usually R¹ is hydrogen or C₁₋₆alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl,alkoxycarbonyl or acyl. Preferably R¹ is hydrogen, methyl, cyanomethyl,2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl,3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. More preferably R¹ ishydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropylor 2-propynyl. Most preferably R¹ is hydrogen.

Generally R² is hydrogen or C₁₋₄ alkyl. Usually R² is hydrogen orunsubstituted C₁₋₄ alkyl. Preferably R² is hydrogen, methyl or n-butyl.More preferably, R² is methyl.

Generally R³ is a group of formula —CHR⁵R⁶ or a benzyl group. PreferablyR³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl. Most preferably R³ is 1-(ethoxycarbonyl)propyl.

Generally R⁴ is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl,C₃₋₆ cycloalkyl, aryl or heterocycle. Usually R⁴ is C₁₋₈ alkyloptionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl,methoxyphenyl, nitrophenyl, aminosulfonylphenyl,3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. PreferablyR⁴ is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. More preferably R⁴is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. Most preferably R⁴is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Generally R⁵ is C₂₋₄ alkyl. Usually R⁵ is unsubstituted C₂₋₄4 alkyl.Preferably R⁵ is ethyl.

Generally R⁶ is C₂₋₄ alkyl, amido or —COOR⁷. Usually R⁶ is unsubstitutedC₂₋₄ alkyl, amido or —COOR⁷. Preferably R⁶ is ethyl, amido orethoxycarbonyl. Most preferably R⁶ is ethoxycarbonyl.

Generally R⁷ is C₁₋₄ alkyl. Usually R⁷ is unsubstituted C₁₋₄ alkyl.Preferably, R⁷ is ethyl.

In some embodiments, the compounds are those having formula I, and theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

wherein

R¹ is hydrogen, C₁₋₆ alkyl optionally substituted by hydroxy, alkoxy,cyano, ethynyl, alkoxycarbonyl or acyl;

R² is hydrogen or unsubstituted C₁₋₄ alkyl;

R³ is a group of formula —CHR⁵R⁶ or a benzyl group;

R⁴ is C₁₋₈ alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl;

R⁵ is unsubstituted C₂₋₄ alkyl;

R⁶ is unsubstituted C₂₋₄ alkyl, amido or —COOR⁷;

R⁷ is unsubstituted C₁₋₄ alkyl;

with the proviso that when R¹ is hydrogen, R² is methyl, R³ is —CHR⁵R⁶,R⁶ is ethoxycarbonyl and R⁵ is ethyl, then R⁴ is different fromn-propyl, i-propyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl,4-methylbenzyl or 2-phenylethyl.

In the above embodiment, preferably, when R³ is a benzyl group, then R⁴is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, preferably, when R³ is a group of formula—CHR⁵R⁶, then R⁴ is C₁₋₈ alkyl optionally substituted by C₃₋₆cycloalkyl, aryl or heterocycle.

In a preferred embodiment,

R¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-pentyl or n-hexyl;

R² is hydrogen, methyl or n-butyl;

R³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R⁴ is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl) propyl;

with the proviso that when R¹ is hydrogen, R² is methyl and R³ is1-(ethoxycarbonyl)propyl, then R⁴ is different from n-pentyl,3-bromobenzyl or 2-phenylethyl.

In the above embodiment, preferably, when R³ is 3-bromobenzyl, then R⁴is C₁₋₈ alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, preferably, when R³ is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R⁴ isdifferent from 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment,

R¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl,3-hydroxypropyl or 2-propynyl;

R² is methyl;

R³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;

R⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that when R¹ is hydrogen, R² is methyl and R³ is1-(ethoxycarbonyl)propyl, then R⁴ is different from 3-bromobenzyl.

In the above embodiment, preferably, when R³ is 3-bromobenzyl, then R⁴is 1-(ethoxycarbonyl)propyl; In the above embodiment, preferably, whenR³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl,then R⁴ is different from 1-(ethoxycarbonyl)propyl;

In a most preferred embodiment, R¹ is hydrogen; R² is methyl; R³ is1-(ethoxycarbonyl)propyl; and R⁴ is 3-methoxybenzyl, 3-nitrobenzyl or(5-nitro-2-furyl)methyl.

A further embodiment consists in compounds wherein R² is methyl, R³ is agroup of formula —CHR⁵R⁶ with R⁵ being C₂₋₄ alkyl, R⁶ being amido or—COOR⁷ and R⁷ being methyl or ethyl.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6₁7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate;and ethyl2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyi2-({3-methyi-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments, compounds useful in the methods and compositions ofthis invention are selected from the group consisting of: ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;and ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

In some embodiments, the compounds are those having formula II, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts:

wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is hydrogen or C.sub.1-4 alkyl;R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl;

In the above embodiment, in some cases, when R.sup.3 is a benzyl group,then R.sup.4 is C.sub.1-8 alkyl optionally substituted byalkoxycarbonyl.

In the above embodiment, in some cases, when R.sup.3 is a group offormula —CHR.sup.5R.sup.6, then R.sup.4 is C.sub.1-8 alkyl optionallysubstituted by C.sub.3-6 cycloalkyl, aryl or heterocycle.

In some embodiments, the compounds are those compounds of formula II,their enantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts

whereinR.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is hydrogen or C.sub.1-4 alkyl;R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl.

In some embodiments, the compounds are compounds of formula II selectedfrom ethyl2-[(7-heptyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;7-(3-bromobenzyl)-3-methyl-8-(propylthio)-3,7-dihydro-1H-purine-2,-6-dione;ethyl2-[(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}butanoate;ethyl2-[(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]but-anoate;7-(3-bromobenzyl)-8-[(3-chloro-2-hydroxypropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}propanoate.

In some embodiments, the compounds are compounds of formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts

whereinR.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl; R.sup.3 is a group of formula—CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is C.sub.2-4 alkyl;R.sup.6 is C.sub.2-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl;

In another embodiment, the compounds are compounds having formula II,their enantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

whereinR.sup.1 is hydrogen or C.sub.1-6 alkyl;R.sup.2 is hydrogen or C.sub.1-4 alkyl;R.sup.3 is a group of formula —CHR.sup.5R.sup.6 or a benzyl group;R.sup.4 is C.sub.1-8 alkyl optionally substituted by alkoxycarbonyl,C.sub.3-6 cycloalkyl, aryl or heterocycle;R.sup.5 is hydrogen or C.sub.1-4 alkyl;R.sup.6 is C.sub.1-4 alkyl, amido or —COOR.sup.7;R.sup.7 is C.sub.1-4 alkyl;

vi) International Patent Application Publication No. WO2010/144712

In one embodiment, a chemical composition that includes a LEV derivativeof Formula 1 or Formula 2 is disclosed.

n of Formula 2 and L, X, and Y of Formulas 1 and 2 are defined asfollows: a) n is an integer with a value of 0 to 8; b) L is one of thegroup consisting of CH2, CO, NHCO, NHCOO, CONH, NH, O, or S, andcombinations thereof; c) X is an end group, an aromatic group, an arylgroup, or a saturated, unsaturated, substituted, unsubstituted, straightchain, or branched chain aliphatic group having from 1 to 10 carbonand/or hetero chain atoms, the hetero chain atoms being selected fromthe group consisting of oxygen, nitrogen, sulfur, or phosphorus, andcombinations thereof; and d) Y is optional and if present is one of afunctional group selected from group consisting of alcohol amine, amide,carboxylic acid, aldehyde, ester, iminoester, isocyanate,isothiocyanate, anhydride, thiol, thiolacetone, diazonium, NHS, CO—NHS,O—NHS, maleimido; or e) Y is a Yi-Z where Yi is selected from the groupconsisting of COO, CO, O, CONH, NHCO, or NH and Z is an operative group.

In one embodiment of the method, the operative group of Z is selectedfrom the group consisting of detectable labels, antigenic carriers,coupling agents, end groups, proteins, lipoproteins, glycoproteins,polypeptides, polysaccharides, nucleic acids, polynucleotides, teichoicacids, radioactive isotopes, enzymes, enzyme fragments, enzyme donorfragments, enzyme acceptor fragments, enzyme substrates, enzymeinhibitors, coenzymes, fluorescent moieties, phosphorescent moieties,anti-stokes up-regulating moieties, chemiluminescent moieties,luminescent moieties, dyes, sensitizers, particles, microparticles,magnetic particles, solid supports, liposomes, ligands, receptors,hapten radioactive isotopes, and combinations thereof

vii) International Patent Application Publication No. WO2010/002869

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Z isindependently selected from hydrogen and deuterium; R1 is an n-propylgroup having zero to seven deuterium atoms; R2 is an ethyl group havingzero to five deuterium atoms, and when each R has zero deuterium atoms,at least one Z is deuterium. One embodiment of this invention providescompounds of Formula I wherein R1 is selected from CD3CH2CH2-,CD3CD2CH2-, CD3CH2CD2-, CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- orCH3CH2CH2-. In a more specific embodiment, R1 is CD3CD2CD2- orCD3CD2CH2-. In one aspect of these embodiments, Z1 and Z2 are bothhydrogen. In another aspect of these embodiments, Z1 and Z2 are bothdeuterium. In another embodiment, R2 is selected from CH3CH2-, CD3CH2-,CH3CD2-, or CD3CD2-. In a more specific embodiment, R2 is selected fromCH3CH2- or CD3CD2-. In one aspect of these embodiments, Z1 and Z2 areboth hydrogen. In another aspect of these embodiments, Z1 and Z2 areboth deuterium.

The R and Z variables as described above may be selected and takentogether to provide more specific embodiments of this invention. Forexample, in one embodiment, R1 is CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-,CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or CH3CH2CH2-; and R2 is selectedfrom CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of thisembodiment, R2 is CH3CH2- or CD3CD2-. [0039] In another embodiment, R1is CD3CD2CD2- or CD3CD2CH2-; and R2 is selected from CH3CH2-, CD3CH2-,CH3CD2-, or CD3CD2-. In one aspect of this embodiment, R2 is CH3CH2- orCD3CD2-.

Examples of specific compounds of this invention include the following:

viii) 20090312333

The compounds of the present invention are those covered by formula (I),their diastereomers and mixtures, or a pharmaceutically acceptable saltthereof.

R1 is hydrogen, substituted or unsubstituted C1-12 alkyl, substituted orunsubstituted aryl or substituted or unsubstituted 3-8 memberedheterocycle.R2 is hydrogen. Alternatively, R1 and R2 may be linked together in sucha way to form a C3-6 cycloalkyl.R3 is either

(a) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its C atoms, said heterocycle is selected from thegroup consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl;-   or R3 is

(b) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its N atoms, said heterocycle is selected from thegroup consisting of:

-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

R4 in formula (I) is selected from the group comprising or consisting ofhydrogen; C1-12 alkyl optionally substituted by halogen, C1-4 alkoxy,C1-4 alkylthio, azido, nitrooxy or an aryl; C2-12 alkenyl optionallysubstituted by halogen; C2-12 alkynyl optionally substituted by halogen;azido; alkoxycarbonylamino; arylsulfonyloxy; a substituted orunsubstituted aryl; or a 3-8 membered substituted or unsubstitutedheterocycle;

In a specific embodiment R4 is hydrogen; or R4 is C1-12 alkyl or a C1-6alkyl, optionally substituted by halogen, C1-4 alkoxy, C1-4 alkylthio,azido or nitrooxy; or R4 is C2-12 alkenyl or a C1-6 alkenyl optionallysubstituted by halogen; or R4 is C2-12 alkynyl or a C1-6 alkynyloptionally substituted by halogen; or R4 is alkoxycarbonylamino.

R5 is hydrogen;

Alternatively R4 may form together with R5 and the 2-oxo-1-pyrrolidinering a 1,3-dihydro-2H-indol-2-one ring of the following structure:

The asterisk * indicates the point of attachment of the substituents;

R6 is hydrogen or halogen.R7 in formula (I) is selected from the group comprising or consisting ofhydrogen; nitro; halogen; heterocycle; amino; aryl; C1-12 alkyloptionally substituted by at least one halogen; or C1-12 alkoxyoptionally substituted by at least one halogen.R8 in formula (I) is selected from the group comprising or consisting ofhydrogen, C1-12 alkyl optionally substituted by halogen, or halogen.R9 in formula (I) is selected from the group comprising or consisting ofhydrogen, C1-12 alkyl optionally substituted by halogen, or halogen.

A further aspect of the present invention consists in compounds offormula (I) wherein

R1 and R2 are both hydrogen.

R3 is:

(a) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its C atoms selected from the group consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl.

Alternatively R3 is:

(b) a substituted or unsubstituted heterocycle linked to the rest of themolecule via one of its N atoms selected from the group consisting of:

-   1H-1,2,3-benzotriazol-1-yl;-   1H-imidazo[4,5-b]pyridin-1-yl;-   3H-imidazo[4,5-b]pyridin-3-yl;-   7H-imidazo[4,5-c]pyridazin-7-yl;-   1H-indol-1-yl;-   2,3-dihydro-1H-indol-1-yl;-   9H-purin-9-yl;-   1H-pyrazolo[3,4-b]pyridin-1-yl;-   2H-pyrazolo[3,4-b]pyridin-2-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   3,4-dihydroquinolin-1(2H)-yl;-   8H-isothiazolo[5,4-b]indol-8-yl;-   1H-1,2,4-triazol-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

R4 in formula (I) is selected from the group comprising or consisting ofhydrogen; C1-12 alkyl optionally substituted by halogen or C1-4 alkoxy;C2-12 alkenyl optionally substituted by halogen; C2-12 alkynyloptionally substituted by halogen. In a further specific embodiment R4is n-propyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2bromo-2,2-difluoroethyl, 2,2-difluorovinyl.

In another specific embodiment R4 is phenyl, 2,3,5-trifluorophenyl or3-chloro-4-fluorophenyl.

R5 is hydrogen;

A further embodiment of the present invention consists in compounds offormula (I) wherein R4 forms together with R5a1,3-dihydro-2H-indol-2-one ring

The asterisk * indicates the point of attachment of the heteroarylalkylene substituent, and wherein

R6 is hydrogen;R7 is chlorine;R8 is hydrogen;R9 is hydrogen.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its C atoms and isselected from the group consisting of:

-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;    -   indolizin-3-yl.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of:

-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;

Said heterocycles are optionally substituted by e.g. a methyl, n-propyl,trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, iodine,methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino,cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzylor 3-thienyl.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl,6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl,6-chloroimidazo[2,1-b][1,3]thiazol-5-yl,2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl, 5-chloro-1H-imidazol-4-yl,5-bromo-1H-imidazol-4-yl, 4-bromo-1H-imidazol-5-yl,4-chloro-1H-imidazol-5-yl, 1H-imidazol-5-yl, 1-methyl-1H-imidazol-5-yl,4-chloro-1-methyl-1H-imidazol-5-yl, 1H-pyrazol-4-yl,1H-pyrrolo[2,3-b]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a heterocycle linked to the rest of themolecule via one of its C atoms and is a substituted or unsubstitutedimidazo[1,2-a]pyridin-3-yl.

Said imidazo[1,2-a]pyridin-3-yl is optionally substituted by e.g. amethyl, cyclopropyl, bromine, chlorine, fluorine, iodine.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of: imidazo[1,2-a]pyridin-3-yl,6-methylimidazo[1,2-a]pyridin-3-yl, 2-chloroimidazo[1,2-a]pyridin-3-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R3 is a substituted or unsubstituted heterocyclelinked to the rest of the molecule via one of its N atoms and isselected from the group consisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-indol-1-yl;-   1H-pyrrolo[2,3-b]pyridin-1-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl.

A specific further embodiment of the present invention consists incompounds of formula (I) wherein R3 is a heterocycle linked to the restof the molecule via one of its N atoms and is selected from the groupconsisting of:

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl;-   2-chloro-1H-benzimidazol-1-yl;

Said heterocycles may optionally be substituted by trifluoromethyl,cyclopropyl, bromine, chlorine, fluorine, methoxy or cyano.

In a further specific embodiment R3 is a heterocycle linked to the restof the molecule via one of its C atoms and is selected from the groupconsisting of 6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl,6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl,1H-pyrrolo[3,2-b]pyridin-1-yl, 2,5-dichloro-1H-pyrrol-1-yl,2-chloro-5-methoxy-1H-benzimidazol-1-yl,5-bromo-2-chloro-1H-benzimidazol-1-yl or2,5-dichloro-1H-benzimidazol-1-yl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R1, R2 and R5 are hydrogen.

R4 is a C1-6 alkyl optionally substituted by halogen, a C2-6 alkenyloptionally substituted by halogen or C2-12 alkynyl optionallysubstituted by halogen.

R3 is selected from the group consisting of

-   imidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-pyrazol-4-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1,3-thiazol-5-yl;    and optionally substituted by methyl, n-propyl, trifluoromethyl,    cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy,    propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy,    cyclobutylmethoxy, amino, methylamino, cyclopropylamino,    cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzyl or 3-thienyl.

A further embodiment of the present invention consists in compounds offormula (I) wherein R1, R2 and R5 are hydrogen.

R4 is a C1-6 alkyl optionally substituted by halogen, a C2-6 alkenyloptionally substituted by halogen or C2-12 alkynyl optionallysubstituted by halogen.

R3 is selected from the group consisting of

-   3H-imidazo[4,5-b]pyridin-3-yl;-   1H pyrrolo[3,2-b]pyridin-1-yl;-   1H-pyrrol-1-yl; 2-chloro-1H-benzimidazol-1-yl;    optionally substituted by trifluoromethyl, cyclopropyl, bromine,    chlorine, fluorine, methoxy or cyano.

A further embodiment of the invention consists in compounds of formula(I), their diastereomers and mixtures, or a pharmaceutically acceptablesalt thereof.

R1, R2 and R5 are hydrogen.

R3 is a substituted or unsubstituted heterocycle linked to the rest ofthe molecule via one of its C atoms, said heterocycle is selected fromthe group consisting of:

-   1H-benzimidazol-6-yl;-   1H-benzimidazol-7-yl;-   imidazo[1,2-a]pyridin-3-yl;-   imidazo[1,2-a]pyrimidin-3-yl;-   imidazo[1,2-b][1,2,4]triazin-7-yl;-   imidazo[1,2-b]pyridazin-3-yl;-   5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;-   imidazo[2,1-b][1,3,4]thiadiazol-5-yl;-   imidazo[2,1-b][1,3]thiazol-5-yl;-   3H-imidazo[4,5-b]pyridin-7-yl;-   1H-imidazol-4-yl;-   1H-imidazol-5-yl;-   1H-indol-2-yl;-   1H-indol-3-yl;-   1H-indol-4-yl;-   1H-indol-7-yl;-   isoxazol-4-yl;-   1H-pyrazol-4-yl;-   1H-pyrazol-5-yl;-   1H-pyrazolo[1,5-a]pyrimidin-3-yl;-   1H-pyrazolo[3,4-b]pyridin-3-yl;-   pyridazin-4-yl;-   pyridin-2-yl;-   pyridin-3-yl;-   pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-3-yl;-   1H-pyrrolo[2,3-b]pyridin-4-yl;-   1H-pyrrolo[2,3-b]pyridin-5-yl;-   1H-pyrrolo[2,3-c]pyridin-2-yl;-   1H-pyrrolo[2,3-c]pyridin-3-yl;-   1H-pyrrolo[3,2-b]pyridin-3-yl;-   1H-pyrrolo[3,2-c]pyridin-2-yl;-   1H-pyrrolo[3,2-c]pyridin-3-yl;-   1,3,4-thiadiazol-2-yl;-   1,3-thiazol-5-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-7-yl;-   [1,2,4]triazolo[4,3-b]pyridazin-8-yl;-   indolizin-3-yl;

Particularly preferred are imidazo[1,2-a]pyridin-3-yl;imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b]pyridazin-3-yl;1H-imidazol-4-yl; 1H-imidazol-5-yl;

R4 is a substituted or unsubstituted phenyl moiety;

A further embodiment of the present invention consists in compounds offormula (I) wherein R1 is hydrogen or C1-12 alkyl;

R2 is hydrogen;R3 is an aromatic 5-membered heterocycle linked to the rest of themolecule via one of its C atoms;R4 is hydrogen, C1-12 alkyl or aryl;R5 is hydrogen;

Alternatively, R4 can form together with R5 and the 2-oxo-1-pyrrolidinering the following 1,3-dihydro-2H-indol-2-one cycle

wherein the asterisk * indicates the point of attachment of thesubstituents;R6 is hydrogen or halogen;

In this embodiment R4 may not be hydrogen when R3 is substituted1H-pyrazol-5-yl. Also this embodiment does not comprise5-(2′-oxo-1′-pyrrolidinyl)methyl-1,3,4-tricarbomethoxy-pyrazole which isdisclosed in A. Padwa et al J. Org. Chem. 2000, 65, 5223-5232 withoutany biological activity though.

In this embodiment wherein R3 is an aromatic 5-membered heterocyclelinked to the rest of the molecule via one of its C atoms, specificmoieties R3 may be selected from 1,3-thiazol-5-yl, 1H-imidazol-4-yl,1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,2-oxo-2,3-dihydro-1,3-thiazol-5-yl, each of them being optionallysubstituted by 1 to 3 substituents independently selected from methyl,chlorine, bromine, amino, methylamino, dimethylamino,(2-oxo-4-propyl-pyrrolidin-1-yl)methyl, 1-pyrrolidinyl, amido, cyano,methoxy, phenyl, 4-methylphenyl-sulfonyl, benzyl or2-(benzylamino)-2-oxoethyl.

In this embodiment, more specific moieties R3 are selected from2-(methylamino)-1,3-thiazol-5-yl; 2-pyrrolidin-1-yl-1,3-thiazol-5-yl;5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;1-methyl-1H-imidazol-5-yl; 4-bromo-1-methyl-1H-imidazol-5-yl;4-chloro-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;4-cyano-1-methyl-1H-imidazol-5-yl; 1H-pyrazol-4-yl;3,5-dimethyl-1H-pyrazol-4-yl; 3-methyl-1H-pyrazol-4-yl.

In this embodiment, most specific moieties R3 are selected from5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl;4-bromo-1-methyl-1H-imidazol-5-yl; 4-chloro-1-methyl-1H-imidazol-5-yl;1H-pyrazol-4-yl.

Still in this embodiment, a specific moiety R1 is selected from hydrogenor ethyl.

Still in this embodiment, a specific moiety R4 is selected fromhydrogen, n-propyl, 2,3,5-trifluorophenyl or phenyl.

A further embodiment of the present invention consists in compoundshaving the specific formula (Ia).

In formula (Ia) the substituent R10 is hydrogen; halogen; C1-4 alkyloptionally substituted by at least one halogen; C1-4 alkoxy;methoxycarbonyl; nitro; amino; alkylamino; amido; or alkanoyl-amino.Preferably R10 is hydrogen.

R11 is hydrogen; halogen; C1-4 alkyl optionally substituted by at leastone halogen; C1-4 alkoxy; methoxycarbonyl; nitro; amino; alkylamino;amido; or alkanoylamino. Preferably R11 is hydrogen.

R4 is C1-4 alkyl optionally substituted by at least one halogen; or C2-4alkenyl optionally substituted by at least one halogen. Preferably R4 isn-propyl.

Still in this aspect of the invention a specific embodiment relates toan embodiment wherein R10 is selected from hydrogen; methyl; fluorine;chlorine; bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl,while R11 is selected from hydrogen; methyl; fluorine; chlorine;bromine; methoxy; methoxycarbonyl; nitro; or trifluoromethyl; and R3 isn-propyl.

Specific compounds of the present invention are those selected from thegroup consisting of:

-   1-[(1-methyl-1H-benzimidazol-6-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-benzimidazol-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2-one;

1-[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

-   1-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(8-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-iodoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(7-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dibromoimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6,8-dichloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propyl    pyrrolidin-2-one;-   1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-phenylimidazo[1,2-b][1,2,4]triazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[1,2-b]pyridazin-3-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-phenylpyrrolidin-2-one;-   5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-1,3-dihydro-2H-indol-2-one;-   1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(dimethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-chloro-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(ethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[6-pyrrolidin-1-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2-bromo-2,2-difluoroethyl)-1-{[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-(isopropylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2-fluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2,2-difluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-({2-cyclopropyl-6-[(2,2,2-trifluoroethyl)amino]imidazo[1,2-b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[2-cyclopropyl-6-(cyclopropylamino)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(3-chloro-4-fluorophenyl)pyrrolidin-2-one;-   1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-ethoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-{[6-(cyclopropylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclobutylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2-(trifluoromethyl)imidazo[1,2-b]pyridazine-6-carbonitrile;-   4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-{[6-pyridin-3-yl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-phenylpyrrolidin-2-one;-   4-phenyl-1-[(5-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7-yl]methyl}pyrrolidin-2-one;-   1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-imidazol-4-yl)propyl]pyrrolidin-2-one;-   1-[(5-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-[(2-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;-   1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-4-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-imidazol-4-yl)methyl]-5-chloro-1,3-dihydro-2H-indol-2-one;-   1-(1H-imidazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-methyl-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-(1H-imidazol-5-ylmethyl)-4-phenylpyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;-   1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carbonitrile;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-4-carboxamide;-   N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide;-   1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile;-   1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-methyl-5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   benzyl    1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-2-ylcarbamate;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one;-   5-chloro-1-(1H-imidazol-5-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   1-[(2,4-dichloro-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-chloro-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-indol-2-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-3-ylmethyl)-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-5-carbonitrile;-   1-[(2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-methoxy-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(trifluoromethyl)-1H-indol-3-yl]methyl}pyrrolidin-2-one;-   1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(7-fluoro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[1H-indol-3-yl(phenyl)methyl]-4-propylpyrrolidin-2-one;-   1-[1-(1H-indol-3-yl)propyl]-4-propylpyrrolidin-2-one;-   1-[2-furyl(1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;-   3-[(2-oxo-4-propylpyrrolidin-1-yl)(phenyl)methyl]-1H-indole-5-carbonitrile;-   1-(1H-indol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-indol-7-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(1-phenyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   4-(2,3,5-trifluorophenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one;-   1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-chloro-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(3-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   (−)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   (+)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;-   5-chloro-1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-1,3-dihydro-2H-indol-2-one;-   1-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(5-amino-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-(1H-pyrazol-5-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(1H-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-({6-[(1E)-hex-1-enyl]-2-methylpyrazolo[1,5-a]pyrimidin-3-yl}methyl)-4-propylpyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-hydroxy-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5,6-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   4-(2,2-difluorovinyl)-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-{[6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   4-propyl-1-(pyridin-3-ylmethyl)pyrrolidin-2-one;-   (−)-1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one;-   5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;-   1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   1-[(2-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-[(2-propyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyrrolidin-2-one;-   1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)pyrrolidin-2-one;-   4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one;-   1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one;-   1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one;-   1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   1-[(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;-   5-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1,3-thiazol-2(3H)-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-7-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7-yl)methyl]pyrrolidin-2-one;-   4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}pyrrolidin-2-one;-   4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]pyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-{[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-8-yl]methyl}-4-phenylpyrrolidin-2-one;-   1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4-phenylpyrrolidin-2-one;-   1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(3-chloro-7H-imidazo[4,5-c]pyridazin-7-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(2,3-dihydro-1H-indol-1-ylmethyl)-4-propylpyrrolidin-2-one;-   1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-2-carbonitrile;-   1-[(2-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(9H-purin-9-ylmethyl)pyrrolidin-2-one;-   1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[6-(benzylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one;-   4-propyl-1-{[6-(propylamino)-9H-purin-9-yl]methyl}pyrrolidin-2-one;-   1-({6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}methyl)-4-propylpyrrolidin-2-one;-   4-propyl-1-[(6-pyrrolidin-1-yl-9H-purin-9-yl)methyl]pyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl]-4-propylpyrrolidin-2-one;-   4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)pyrrolidin-2-one;-   1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(8H-isothiazolo[5,4-b]indol-8-ylmethyl)-4-propylpyrrolidin-2-one;-   1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one;-   1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;-   2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-6-carbonitrile;-   4-propyl-1-[(2,5,6-trichloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-nitro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;-   1-[(6-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(5-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-6-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2-chloro-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,6-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-[(2,5-dichloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-{[2-chloro-6-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-{[2-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;-   1-[(2-chloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;-   1-[(2-chloro-6-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;-   1-(pyridin-4-ylmethyl)pyrrolidin-2-one, and-   1-[(2-chloro-5-hydroxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one.

viii) U.S. Pat. No. 4,696,943

The present invention relates to the novel compound(S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

ix) U.S. Pat. No. 4,696,942

The present invention relates to the novel compound,(R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

x) U.S. Pat. No. 5,334,720

According to this invention we provide novel compounds of the formula I,

wherein, R1, R2, R3 and R4, which may be the same or differentindependently represent hydrogen, C1-6 alkyl, phenyl or phenylsubstituted by one or more halogen, hydroxyl, nitro, amino, C1-6 alkylor C1-C6 alkoxy groups;R5 and R6 independently represent hydrogen, C1-C6 alkyl or C3-C6cycloalkyl, or R5 and R6 together with the nitrogen form a C4-6 Nheterocycle;m represents an integer from 1-2; andn represents an integer from 1-3;provided that,two of the substituents R1, R2, R3 and R4 independently represent phenylor substituted phenyl and the other two independently represent hydrogenor C1-6 alkyl;or a pharmaceutically acceptable acid addition salt thereof.

Pharmaceutically acceptable acid addition salts of the compounds offormula I include salts of mineral acids, for example, hydrohalic acids,e.g. hydrochloric or hydrobromic; organic acids, e.g. formic, acetic orlactic acids. The acid may be polybasic, for example sulphuric, fumaric,maleic or citric acid.

This invention also relates to all stereoisomeric forms and opticalenantiomeric forms of the compounds of formula I.

In the compounds of formula I: alkyl groups which R1, R2, R3, R4, R5 andR6 may represent include methyl, ethyl, propyl, isopropyl, n-butyl,iso-butyl and s-butyl;

cycloalkyl groups which R5 and R6 may represent include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl;C1-6 alkoxy groups include methoxy, ethoxy and propoxy;halogen groups include fluorine, chlorine, bromine or iodine;

We prefer compounds of formula I or a pharmaceutically acceptable acidaddition salt thereof, in which;

R1 is hydrogen, phenyl or substituted phenyl, preferably phenyl;R2 is hydrogen, phenyl or substituted phenyl, preferably phenyl;R3 is hydrogen, phenyl or substituted phenyl, preferably hydrogen;R4 is hydrogen, phenyl or substituted phenyl, preferably hydrogen;R5 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen ormethyl;R6 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydrogen ormethyl;m represents an integer from 1-2 preferably 2;n represents an integer from 1-2, preferably 1.

We especially prefer compounds of formula I in which R1 and R2 are bothphenyl.

We especially prefer compounds of formula I in which one of R5 and R6 ishydrogen and the other is hydrogen or methyl.

xi) International Patent Application Publication No. WO2005/054188

In one aspect the invention therefore provides a compound having theformula I or a pharmaceutically acceptable salt thereof,

whereinRI is hydrogen, CI-20 alkyl, C3 23 cycloalkyl, halogen, hydroxy, alkoxy,aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative,alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,arylsulfinyl, aryl or heterocycle; R2 is hydrogen, C1 20 alkyl, alkoxy,amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;R3 is hydrogen, C1 20 alkyl, alkoxy, amino, halogen, hydroxy, ester,amido, nitro, cyano, carbamate, or aryl;or R2 and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R4 is hydrogen, C1-20 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl, azido,alkoxycarbonylamino, arylsulfonyloxy or heterocycle; R4a is hydrogen orC1-20 alkyl; or R4 and R4a can form together a C3-8 cycloalkyl; R5 ishydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R6 is hydrogen or C1 20 alkyl; R7 is hydrogen; or R6 and R7 are linkedtogether to form a C3-6 cycloalkyl; R8 is hydrogen, halogen, nitro,cyano, C1 20 alkyl or alkoxy; R9 is hydrogen, C1-20 alkyl, halogen,hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, aminoderivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,alkylsulfinyl or arylsulfinyl;RIO is hydrogen, C1 20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester,amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio,alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;RI 1 is hydrogen, halogen, nitro, cyano, C1 20 alkyl or alkoxy; R12 ishydrogen or halogen;R13 is hydrogen, nitro, halogen, heterocycle, amino, aryl, C1-20 alkylunsubstituted or substituted by halogen, or alkoxy unsubstituted orsubstituted by halogen; R14 is hydrogen, C1-20 alkyl or halogen;R15 is hydrogen, C1 20 alkyl or halogen;with the proviso that R4 is different from hydrogen when

N represents a group of formula

The asterisk * indicates the point of attachment of the substituents.

In a preferred embodiment, the invention concerns a compound having theformula I, their tautomers, geometrical isomers (including cis andtrans, Z and E isomers), enantiomers, diastereoisomers and mixturesthereof (including all possible mixtures of stereoisomers), orpharmaceutically acceptable salts thereof,

whereinRI is hydrogen, C1-20 alkyl, C3-8 cycloalkyl, halogen, hydroxy, ester,amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl,alkylsulfinyl, aryl or heterocycle; R2 is hydrogen, C1 20 alkyl,halogen, cyano, ester, carbamate or amido; R3 is hydrogen, cyano, C 1 20alkyl, halogen or ester; or R2 and R3 can form together with theimidazole ring the following 1H-benzimidazole cycle

is hydrogen, C1 20 alkyl, C2 12 alkenyl or aryl; R4a is hydrogen;R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R6 is hydrogen or C 1 20 alkyl; R7 is hydrogen; or R6 and R7 are linkedtogether to form a C3-6 cycloalkyl; R8 is hydrogen; R9 is hydrogen,C1-20 alkyl, halogen or alkoxy; RIO is hydrogen, C1 20 alkyl, halogen orcyano; R11 is hydrogen; R12 is hydrogen or halogen; R13 is hydrogen,halogen, heterocycle or C1 20 alkyl; R14 is hydrogen; R15 is hydrogen;with the proviso that R4 is different from hydrogen when

represents a group of formula

The term“alkyl”, as used herein, represents saturated, monovalenthydrocarbon radicals having straight (unbranched) or branched or cyclicor combinations thereof and containing 1-20 carbon atoms, preferably1-10 carbon atoms, more preferably 1-4 carbon atoms; most preferredalkyl groups have 1-3 carbon atoms. Alkyl moieties may optionally besubstituted by 1 to 5 substituents independently selected from the groupconsisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy,alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl or aryl. Usually alkylgroups, in the present case, are methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, 1-ethylpropyl, n-heptyl,2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl,2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino) methyl,(propionylamino) methyl, (benzoylamino) methyl, (4-chlorophenoxy)methyl,benzyl, 2-phenylethyl or 2-(methylthio)ethyl. Preferred alkyl groups aremethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl,2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl,(acetylamino) methyl, (propionylamino) methyl, (benzoylamino) methyl or2-(methylthio)ethyl. More preferred alkyl groups are methyl, ethyl,n-propyl, i-propyl, n-butyl, azidomethyl or trifluoromethyl. Mostpreferred alkyl groups are methyl or n-propyl.

The term“cycloalkyl”, as used herein, represents a monovalent group of 3to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturatedcyclic hydrocarbon, which may be substituted by any suitable groupincluding but not limited to one or more moieties selected from groupsas described above for the alkyl groups. Preferred cycloalkyl groups arecyclopropyl and cyclohexyl.

The term“alkenyl” as used herein, represents straight, branched orcyclic unsaturated hydrocarbon radicals or combinations thereof havingat least one carbon-carbon double bond, containing 2-12 carbon atoms,preferably usually 2-4 carbon atoms. Alkenyl groups are being optionallysubstituted with any suitable group, including but not limited to one ormore moities selected from groups as described above for the alkylgroups. Usually an alkenyl group is ethenyl (vinyl) optionallysubstituted by 1 to 3 halogens. Preferred alkenyl group, in the presentcase, is 2,2-difluorovinyl.

The term“alkynyl” as used herein, represents straight, branched orcyclic hydrocarbon radicals or combinations thereof containing at leastone carbon-carbon triple bond, containing 2-12 carbon atoms, preferably2-6 carbon atoms, and being optionally substituted by any suitablegroup, including but not limited to one or more moities selected fromgroups as described above for the alkyl groups. Preferably an alkynylgroup is a halogenoalkynyl group (haloalkynyl group).

Groups qualified by prefixes such as“s”, “i”, “t” and the like (e.g.“i-propyl”, “s-butyl”) are branched derivatives.

The term “aryl” as used herein, is defined as phenyl optionallysubstituted by 1 to 4 substituents independently selected from halogen,cyano, alkoxy, alkylthio, C1 3 alkyl or azido, preferably halogen orazido. Usually aryl groups, in the present case are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or3-azido-2,4,6-trifluorophenyl. Preferably, aryl groups are phenyl,3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferred arylgroups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl,2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl,3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cycloalkyl moiety as defined above, having atleast one O, S and/or N atom interrupting the carbocyclic ringstructure. Heterocyclic ring moities can be optionally substituted byalkyl groups or halogens and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl. Usuallyheterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl,1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl,4-chloro-1-methyl-1H-pyrazol-3-yl,5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl,3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl,4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. Preferredheterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl,1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2-yl,1H-pyrrol-2-yl.

The term “halogen”, as used herein, includes an atom of chlorine,bromine, fluorine, iodine. Usually halogens are chlorine, bromine andfluorine. Preferred halogens are fluorine, bromine and chlorine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “alkoxy”, as used herein, represents a group of formula —ORawherein Ra is an alkyl group, as defined above. Preferred alkoxy groupis methoxy.

The term “aryloxy”, as used herein, represents a group of formula —ORbwherein Rb is an aryl group, as defined above. Preferred aryloxy groupis phenoxy.

The term “ester”, as used herein, represents a group of formula —COORCwherein Rc is an alkyl group or aryl group, as defined above. Preferredester group is methoxycarbonyl.

The term “amido”, as used herein, represents a group of formula —CONH2.

The term “amino”, as used herein, represents a group of formula —NH2.

The term “aminoderivative”, as used herein, represents an alkylamino oran arylamino group, wherein the terms “alkyl” and “aryl” are defined asabove.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “nitro”, as used herein, represents a group of formula —N02.

The term “azido”, as used herein, represents a group of formula —N3.

The term “guanidine”, as used herein, represents a group of formula—NHC(═NH)NH2.

The term “alkylthio”, as used herein, represents a group of formula —SRdwherein Rd is an alkyl group, as defined above. One alkylthio group ismethylthio.

The term “alkylsulfonyl”, as used herein, represents a group of formula—S(═O)2Re wherein Re is an alkyl group, as defined above. Onealkylsulfonyl group is methylsulfonyl.

The term “alkylsulfinyl”, as used herein, represents a group of formula—S(═O)Rf wherein Rf is an alkyl group, as defined above. Onealkylsulfinyl group is methylsulfinyl.

The term “arylthio”, as used herein, represents a group of formula —SRgwherein Rg is an aryl group, as defined above.

The term “arylsulfonyl”, as used herein, represents a group of theformula —S(═O)2Rh wherein Rh is an aryl group, as defined above.

The term “arylsulfinyl”, as used herein, represents a group of theformula —S(═O)Ri wherein Ri is an aryl group, as defined above.

The term “carbamate” as used herein, represents a group of formula—N(H)C(O)OR1, wherein Ri is an alkyl or an aryl, as defined above.Usually carbamate groups are (propoxycarbonyl) amino or(benzyloaxycarbonyl) amino. One carbamate group is (benzyloaxycarbonyl)amino.

The term “alkanoylamino” as used herein, represents a group of theformula —NHC(═O)Rk wherein Rk is an alkyl group, as defined above.

The term “(arylcarbonyl) amino” as used herein, represents a group ofthe formula —NHC(═O)Rm wherein Rm is an aryl group, as defined above.One (arylcarbonyl) amino is benzoylamino.

Usually, RI is hydrogen; C1 lo alkyl unsubstituted or substituted byhalogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy;C3-6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl groups; or guanidine.

In some embodiments, RI is hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl;2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl;2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl; chloro; bromo;nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl;1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. More preferably, RI ishydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl; methylthio; nitro;cyano; amino; chloro or 1H-pyrrol-2-yl. Most preferably, RI is hydrogen;methyl; methylthio; nitro; cyano; amino or chloro.

Usually, R2 is hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably, R2 ishydrogen; methyl; hydroxymethyl; (acetylamino) methyl; (propionylamino)methyl; (benzoylamino) methyl; [(benzyloxy)carbonyl]amino; chloro orcyano. In some embodiments, R2 is hydrogen; chloro or cyano.

Usually, R3 is hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano. In some embodiments, R3 is hydrogen;hydroxymethyl; chloro; cyano.

In some embodiments, R3 is hydrogen or cyano. In some embodiments R3 ishydrogen.

Usually, R4 is hydrogen; C1 4 alkyl unsubstituted or substituted byhalogens; C2 4 alkenyl substituted by halogens or phenyl groupunsubstituted or substituted by azido or/and halogens. Preferably, R4 ishydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl;3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Morepreferably, R4 is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl;3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl;3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl;2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl;3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R4is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or3-azido-2,4-difluorophenyl.

Usually, R4a is hydrogen.

Usually, R5 is hydrogen.

Usually, R6 is hydrogen or C1-1˜0 alkyl unsubstituted or substituted byhydroxy or azido. Preferably, R6 is hydrogen or azidomethyl. Morepreferably R6 is hydrogen.

Usually R7 is hydrogen.

In other embodiments, R6 and R7 are linked to form a cyclopropyl.

In other embodiments, R2 and R3 can form together with the imidazolering the following 1H-benzimidaole cycle

Usually, R8 is hydrogen.

Usually, R9 is hydrogen; halogen; 1-3 alkyl or alkoxy. In someembodiments, R9 is hydrogen; methyl; chloro or methoxy. In someembodiments R9 is hydrogen.

Usually, RIO is hydrogen; halogen; cyano; C1 3 alkyl unsubstituted orsubstituted by halogens; or alkoxy. In some embodiments, RIO is methyl;hydrogen; trifluoromethyl; fluoro; cyano or methoxy. In some embodimentsR10 is hydrogen; trifluoromethyl; fluoro or cyano.

Usually, RI 1 is hydrogen.

In other embodiments, R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

Usually, R12 is hydrogen or halogen. In some embodiments R12 ishydrogen; chloro or fluoro. In some embodiments R12 is hydrogen.

Usually, R13 is hydrogen; C1 3 alkyl; halogen or thiazolyl unsubstitutedor substituted by alkyl groups, such as methylthiazolyl. In someembodiments R13 is hydrogen; chloro; bromo or methyl. In someembodiments R13 is chloro; bromo or methyl.

Usually R14 is hydrogen.

Usually, R15 is hydrogen.

In a general embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salts thereof, are those wherein

RI is selected from hydrogen; C1 lo alkyl unsubstituted or substitutedby halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C3 6cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl;alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle unsubstituted orsubstituted by alkyl group; or guanidine; R2 is selected from hydrogen;C1-4 alkyl unsubstituted or substituted by hydroxy, alkanoylamino orbenzoylamino; halogen; ester; cyano; alkyl carbamate or[(N-methoxy-N-methyl)amino]carbonyl.R3 is selected from hydrogen; C1 4 alkyl unsubstituted or substituted byhydroxy; halogen; ester or cyano; R4 is selected from hydrogen; C1 4alkyl unsubstituted or substituted by halogens; C2 4 alkenyl substitutedby halogens or phenyl group unsubstituted or substituted by azido or/andhalogens;R4a is hydrogen; R5 is hydrogen; R6 is selected from hydrogen or C1-10alkyl unsubstituted or substituted by hydroxy or azido;R7 is hydrogen; or R6 and R7 can be linked to form a cyclopropyl; or R2and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R8 is hydrogen; R9 is selected from hydrogen; halogen; C1-3 alkyl;alkoxy;R10 is selected from hydrogen; halogen; cyano or Cil alkyl unsubstitutedor substituted by halogens; or alkoxy; R1 is hydrogen; or R4, R4a and R5can form together with the 2-oxo-1-pyrrolidine ring the following1,3-dihydro-2H-indol-2-one cycle

R12 is selected from hydrogen or halogen; R13 is selected from hydrogen;CI-3 alkyl; halogen; thiazolyl unsubstituted or substituted by alkylgroups, such as methylthiazolyl; R14 is hydrogen; R15 is hydrogen; withthe proviso that R4 is different from hydrogen when

represents a group of formula

In an embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl;2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl;hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chloro;bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio;methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl;1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl;1,2,3-thiadiazol-4-yl; or 1H-imidazol-2-yl; R2 is selected fromhydrogen; methyl; hydroxymethyl; (acetylamino) methyl; (propionylamino)methyl; (benzoylamino) methyl; (benzyloxycarbonyl) amino; chloro; orcyano; R3 is selected from hydrogen; hydroxymethyl; chloro; cyano; or R2and R3 can form together with the imidazole ring the following1H-benzimidazole cycle

R8 is hydrogen; R9 is selected from hydrogen; methyl; choro; methoxy;R10 is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano;or methoxy; R is hydrogen; R4 is selected from hydrogen; n-propyl;2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl;3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl; or 3-azido-2,4,6-trifluorophenyl. R4a ishydrogen; R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R12 is selected from hydrogen; chloro; fluoro; R13 is selected fromhydrogen; chloro; bromo; methyl; R14 is hydrogen; R15 hydrogen; R6 isselected from hydrogen; azidomethyl; R7 is hydrogen; or R6 and R7 arelinked to form a cyclopropyl; with the proviso that R4 is different fromhydrogen when

represents a group of formula

In one embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl;n-butyl; methylthio; nitro; cyano; amino; chloro; or 1H-pyrrol-2-yl; R2is selected from hydrogen; chloro; cyano; R3 is selected from hydrogen;cyano; or R2 and R3 can form together with the imidazole ring thefollowing 1H-benzimidazole cycle

R8 is hydrogen; R9 is hydrogen;R10 is selected from hydrogen; trifluoromethyl; fluoro; cyano;RI 1 is hydrogen; R4 is selected from hydrogen; n-propyl;2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl;4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl;3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl;2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; or3-azido-2,4-difluorophenyl; R4a is hydrogen; R5 is hydrogen; or R4, R4aand R5 can form together with the 2-oxo-1-pyrrolidine ring the following1,3-dihydro-2H-indol-2-one cycle

wherein R12 is hydrogen; R13 is selected from methyl; chloro; bromo; R14is hydrogen; R15 hydrogen; R6 is hydrogen; R7 is hydrogen; with theproviso that R4 is different from hydrogen when

R11 represents a group of formula

In one embodiment of the invention, the compounds of formula I, orpharmaceutically acceptable salt thereof, are those wherein

RI is selected from hydrogen; methyl; methylthio; nitro; cyano; amino;chloro; R2 is selected from hydrogen; chloro; cyano; R3 is hydrogen; R4is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl;3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl;2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;3-azido-2,4-difluorophenyl; R4a is hydrogen;R5 is hydrogen; or R4, R4a and R5 can form together with the2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

R12 is hydrogen; R13 is selected from chloro; bromo; methyl; R14 ishydrogen; R15 hydrogen; R6 is hydrogen; R7 is hydrogen.

In some embodiments, compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmelthyl)pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmelthyl)pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl) pyrrolidin-2-one;1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;methyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylate;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,4-dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(−)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-ylmethyl}-1H-imidazole-4-carbonitrile;(−)-1-{[2-oxo-4-(3,4,5=trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-methyl}-1H-imidazole-5-carbonitrile;1-[(5-methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2,5-dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyll-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(4-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(2-bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[4-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;benzyl1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-5-ylcarbamate;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide;N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide; N-1(1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrroldin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide;1-(1H-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]melthyl}-4-propylpyrrolidin-2-one;{1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetonitrile;1-[(5-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile;1-[(2-cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-ylmethyl}-4-propylpyrrolidin-2-one;1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl)-1H-benzimidazole-5-carbonitrile;1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]melthyl}pyrrolidin-2-one;1-1[2-(3-furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile;and1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds are: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl) pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-1(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(+1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+);1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile;1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;4-propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one;1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile;1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, compounds are:1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one;(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one;4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;4-(3,5-difluoromethyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl) pyrrolidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl) pyrrolidin-2-one;1-H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl) pyrrolidin-2-one;1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile;1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;(−)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one;1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile;5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one;1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one;1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

Some compounds are:(−)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;(+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

The acid addition salt form of a compound of formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.,45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicity indicated in the above formula areintended to be included within the scope of the present invention.

In another preferred embodiment, the present invention concerns alsocompounds of formula IA and their tautomeric form IB

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically. Compounds according to the presentinvention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

The invention also includes within its scope pro-drug forms of thecompounds of formula I and its various sub-scopes and sub-groups.

xii) U.S. Patent Application Publication No. 20090018148

In one aspect the invention provides compounds having formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

whereinR1 is hydrogen or C1-6 alkyl;R2 is hydrogen or C1-4 alkyl;R3 is a group of formula —CHR5R6 or a benzyl group;R4 is C1-8 alkyl optionally substituted by alkoxycarbonyl, C3-6cycloalkyl, aryl or heterocycle;R5 is C2-4 alkyl;R6 is C2-4 alkyl, amido or —COOR7;R7 is C1-4 alkyl;

In one aspect, the invention provides compounds:

When R1 is hydrogen, R2 is methyl, R3 is —CHR5R6, R6 is ethoxycarbonyland R5 is ethyl, then R4 is different from methyl, n-propyl, i-propyl,n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or2-phenylethyl;

When R1 is hydrogen, R2 is methyl, R3 is benzyl, then R4 is differentfrom i-propyl, n-butyl, 3-methylbutyl, benzyl, phenylethyl-, or3-phenylpropyl; When R1 and R2 are methyl, R3 is benzyl, R4 is differentfrom methyl, 3-methylbutyl, benzyl, 3-phenylpropyl or4-chlorophenylmethyl; Finally8-(2-chloro-benzylsulfanyl)-3-methyl-7-octyl-3,7-dihydro-purine-2,6-dioneis considered.

Usually when R3 is a benzyl group, then R4 is C1-8 alkyl optionallysubstituted by alkoxycarbonyl.

Usually when R3 is a group of formula —CHR5R6, then R4 is C1-8 alkyloptionally substituted by C3-6 cycloalkyl, aryl or heterocycle.

The term “alkyl”, as used herein, is a group which represents saturated,monovalent hydrocarbon radicals having straight (unbranched) or branchedmoieties, or combinations thereof, and containing 1-8 carbon atoms,preferably 1-6 carbon atoms; more preferably alkyl groups have 1-4carbon atoms. Alkyl moieties may optionally be substituted by 1 to 5substituents independently selected from the group consisting ofhydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl orheterocycle. Alkyl moieties may be optionally substituted by acycloalkyl as defined hereafter. Preferred alkyl groups according to thepresent invention are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-butyl, i-butyl, n-pentyl, 3-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl or(5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl,cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl,n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or(5-nitro-2-furyl)methyl. Most preferred alkyl groups are methyl, ethyl,3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

The term “cycloalkyl”, as used herein, represents a monovalent group of3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclichydrocarbon, which may be substituted by any suitable group includingbut not limited to one or more moieties selected from groups asdescribed above for the alkyl groups. Preferred cycloalkyl groupaccording to the present invention is cyclohexyl.

The term “aryl” as used herein, is defined as a phenyl group optionallysubstituted by 1 to 4 substituents independently selected from halogen,amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl,3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

The term “phenyl”, as used herein, represents an aromatic hydrocarbongroup of formula —C6H5.

The term “benzyl group”, as used herein, represents a group of formula—CH2-aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl,3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferred benzyl groupsare benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or3-aminobenzyl. In some embodiments alkyl groups are 3-methoxybenzyl or3-nitrobenzyl.

The term “halogen”, as used herein, represents an atom of fluorine,chlorine, bromine, or iodine. In some embodiments the halogen isbromine.

The term “hydroxy”, as used herein, represents a group of formula —OH.

The term “cyano”, as used herein, represents a group of formula —CN.

The term “amino”, as used herein, represents a group of formula —NH2.

The term “ethynyl”, as used herein, represents a group of formula —C≡CH.

The term “alkoxy”, as used herein, represents a group of formula —ORawherein Ra is an alkyl group, as defined above. In some embodiments thealkoxy group is methoxy.

The term “nitro”, as used herein, represents a group of formula —NO2.

The term “amido”, as used herein, represents a group of formula—C(═O)NH2.

The term “acyl”, as used herein, represents a group of formula —C(═O)Rbwherein Rb is an alkyl group, as defined here above. In some embodimentsthe acyl group is acetyl (—C(═O)Me).

The term “alkoxycarbonyl (or ester)”, as used herein, represents a groupof formula —COORc wherein Rc is an alkyl group; with the proviso that Rcdoes not represent an alkyl alpha-substituted by hydroxy. In someembodiments the alkoxycarbonyl group is ethoxycarbonyl.

The term “heterocycle”, as used herein, represents a 5-membered ringcontaining one or two heteroatoms selected from O or N. The heterocyclemay be substituted by one or two C1-4 alkyl or nitro. In someembodiments the heterocycles are (3,5-dimethylisoxazol-4-yl) or(5-nitro-2-furyl). Most preferred heterocycle is (5-nitro-2-furyl).

Generally R1 is hydrogen or C1-6 alkyl. Usually R1 is hydrogen or C1-6alkyl optionally substituted by hydroxy, alkoxy, cyano, ethynyl,alkoxycarbonyl or acyl. In some embodiments R1 is hydrogen, methyl,cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl,3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. In some embodiments R1is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl,3-hydroxypropyl or 2-propynyl. In some embodiments R1 is hydrogen.

Generally R2 is hydrogen or C1-4 alkyl. Usually R2 is hydrogen orunsubstituted C1-4 alkyl. In some embodiments R2 is hydrogen, methyl orn-butyl. In some embodiments, R2 is methyl.

Generally R3 is a group of formula —CHR5R6 or a benzyl group. In someembodiments R3 is 3-pentyl, 1-(aminocarbonyl)propyl,1-(ethoxycarbonyl)propyl or 3-bromobenzyl. In some embodiments R3 is1-(ethoxycarbonyl)propyl.

Generally R4 is C1-8 alkyl optionally substituted by alkoxycarbonyl,C3-6 cycloalkyl, aryl or heterocycle. Usually R4 is C1-8 alkyloptionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl,methoxyphenyl, nitrophenyl, aminosulfonylphenyl,3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. In someembodiments R4 is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl,benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. In some embodimentsR4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. In some embodimentsR4 is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Generally R5 is C2-4 alkyl. Usually R5 is unsubstituted C2-4 alkyl. Insome embodiments R5 is ethyl.

Generally R6 is C2-4 alkyl, amido or —COOR7. Usually R6 is unsubstitutedC2-4 alkyl, amido or —COOR7. In some embodiments R6 is ethyl, amido orethoxycarbonyl. In some embodiments R6 is ethoxycarbonyl.

Generally R7 is C1-4 alkyl. Usually R7 is unsubstituted C1-4 alkyl. Insome embodiments, R7 is ethyl.

Usually the invention provides compounds having formula I, theirenantiomers, diastereoisomers and mixtures thereof (including allpossible mixtures of stereoisomers), or pharmaceutically acceptablesalts thereof,

whereinR1 is hydrogen, C1-6 alkyl optionally substituted by hydroxy, alkoxy,cyano, ethynyl, alkoxycarbonyl or acyl;R2 is hydrogen or unsubstituted C1-4 alkyl;R3 is a group of formula —CHR5R6 or a benzyl group;R4 is C1-8 alkyl optionally substituted by cyclohexyl, phenyl,bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl,aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl orethoxycarbonyl;R5 is unsubstituted C2-4 alkyl;R6 is unsubstituted C2-4 alkyl, amido or —COOR7;R7 is unsubstituted C1-4 alkyl;with the proviso that when R1 is hydrogen, R2 is methyl, R3 is —CHR5R6,R6 is ethoxycarbonyl and R5 is ethyl, then R4 is different fromn-propyl, i-propyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl,4-methylbenzyl or 2-phenylethyl.

In the above embodiment, sometimes, when R3 is a benzyl group, then R4is C1-8 alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, sometimes, when R3 is a group of formula—CHR5R6, then R4 is C1-8 alkyl optionally substituted by C3-6cycloalkyl, aryl or heterocycle.

In one embodiment,

R1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl,2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl,n-pentyl or n-hexyl;R2 is hydrogen, methyl or n-butyl;R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;R4 is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl,2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl,2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;with the proviso that when R1 is hydrogen, R2 is methyl and R3 is1-(ethoxycarbonyl)propyl, then R4 is different from n-pentyl,3-bromobenzyl or 2-phenylethyl.

In the above embodiment, sometimes, when R3 is 3-bromobenzyl, then R4 isC1-8 alkyl optionally substituted by alkoxycarbonyl.

In the above embodiment, sometimes, when R3 is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R4 isdifferent from 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment, R1 is hydrogen, methyl, cyanomethyl,2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R2 is methyl;R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or3-bromobenzyl;R4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl,3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl,(5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl;with the proviso that when R1 is hydrogen, R2 is methyl and R3 is1-(ethoxycarbonyl)propyl, then R4 is different from 3-bromobenzyl.

In the above embodiment, sometimes, when R3 is 3-bromobenzyl, then R4 is1-(ethoxycarbonyl)propyl;

In the above embodiment, sometimes, when R3 is 3-pentyl,1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R4 isdifferent from 1-(ethoxycarbonyl)propyl;

In one embodiment, R1 is hydrogen; R2 is methyl; R3 is1-(ethoxycarbonyl)propyl; and R4 is 3-methoxybenzyl, 3-nitrobenzyl or(5-nitro-2-furyl)methyl.

A further embodiment consists in compounds wherein R2 is methyl, R3 is agroup of formula —CHR5R6 with R5 being C2-4 alkyl, R6 being amido or—COOR7 and R7 being methyl or ethyl.

In some embodiments, compounds are ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate;and ethyl2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments compounds are: ethyl2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;ethyl2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;ethyl2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide;7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione;and ethyl2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments compounds are: ethyl2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;ethyl2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;and ethyl2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

The acid addition salt form of a compound of formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.,45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically. Compounds according to the presentinvention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

xiii) U.S. Pat. No. 7,465,549

In some embodiments, the compound includes optionally substitutedN-alkylated 2-oxo-pyrrolidine derivatives. In some embodiments, thosecompounds are alkyl amides derivatives substituted on the positions 4and/or 5 of the pyrrolidone ring.

Examples of optionally substituted N-alkylated 2-oxo-pyrrolidinederivatives include, but are not limited to, compounds such as(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide,(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide,(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide, and(2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide.

In some embodiments, the compounds further include optionallysubstituted N-alkylated 2-oxo-piperidinyl derivatives. In someembodiments, those compounds are alkyl amides derivatives substituted onthe position 4 and/or 5 and/or 6 of the 2-oxo-piperidinyl ring. Examplesof optionally substituted N-alkylated 2-oxo-pyrrolidine derivativesinclude, but are not limited to, compounds such as those referred to ininternational patent application PCT/EP02/05503 such as(2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,(2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,(2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, and(2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyrrolidinyl]butanamide.

In some embodiments, the compounds include any acetam compound offormula I, in racemic or isomeric form, or a pharmaceutically acceptablesalt thereof,

whereinR represents hydrogen or hydroxy;R1 and R2 represent independently hydrogen or an alkyl group of 1-4carbon atoms; andR3 and R4 represent independently hydrogen, an alkyl group of 1-4 carbonatoms or —(CH2)n-NR5R6 wherein n is 1, 2 or 3 and R5 and R6 representindependently hydrogen or an alkyl group of 1-4 carbon atoms.

An example of such an acetam compound includes, but is not limited to, acompound of formula I wherein R, R1, R2, R3 and R4 are hydrogen,2-oxo-pyrrolidineacetamide, known by the generic name piracetam asdescribed in UK Patents Nos. 1,039,113 and 1,309,692.

In some embodiments, the compounds also include optionally substitutedN-alkylated 2-oxo-azepanyl derivatives. Preferably, those compounds arealkyl amides derivatives substituted on the positions 4 and/or 5 and/or6 and/or 7 of the 2-oxo-azepanyl ring. Examples of optionallysubstituted N-alkylated 2-oxo-azepanyl derivatives include, but are notlimited to, compounds such as those referred to in international patentapplication PCT/EP02/05503 such as2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xiv) U.S. Patent Application Publication No. 2006258704

This invention provides novel compounds of the formula I

whereinn represents 0 or 1 whereby R<1> is not existent when n=0 and R<1> isexistent when n=1;A<1> represents an oxygen or a sulfur atom;

X is —CONR<7>R<8>, —COOR<9>, —CO—R<10> or CN;

R<1> when existent, R<2>, R<3>, R<4> and R<5> are the same or differentand each is independently hydrogen, halogen, hydroxy, thiol, amino,nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid,sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle,or an oxy derivative, thio derivative, amino derivative, acylderivative, sulfonyl derivative or sulfinyl derivative, provided that atleast one of the substituents R chosen from R<1> when existent,R<2>, R<3>, R<4> or R<5> is not hydrogen;R<6> is hydrogen, alkyl, aryl or —CH2-R<6a> wherein R<6a> is aryl,heterocycle, halogen, hydroxy, amino, nitro or cyano;R<7>, R<8> and R<9> are the same or different and each is independentlyhydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative; andR<10> is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle ora thio derivative;their pharmaceutically acceptable salts, geometrical Isomers (includingcis and trans, Z and E isomers), enantiomers, diastereoisomers andmixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one substituent R<1> to R<5> is differentfrom hydrogen. Some non-substituted compounds are referred to in U.S.Pat. Nos. 5,468,733 and 5,516,759. U.S. Pat. No. 5,468,733 disclosesnon-ring substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinylderivatives as inhibitors of the oncogene Ras protein. In particular,these compounds block the ability of Ras to transform normal cells tocancer cells, and therefore can be included in several chemotherapeuticcompositions for treating cancer.

U.S. Pat. No. 5,516,759 discloses non-ring substituted2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl derivativespresent at the N-terminus of dodecapeptides possessing LHRH (luteinizinghormone-releasing hormone) antagonistic activity. Such LHRH antagonistsare useful in the treatment of a variety of conditions in whichsuppression of sex steroids plays a key role including contraception,delay of puberty, treatment of benign prostatic hyperplasia a.o.

In the definitions set forth below, unless otherwise stated, R<11> andR<12> are the same or different and each is independently amido, alkyl,alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or anoxy derivative, thio derivative, acyl derivative, amino derivative,sulfonyl derivative, or sulfinyl derivative, each optionally substitutedwith any suitable group, including, but not limited to, one or moremoieties selected from lower alkyl or other groups as described below assubstituents for alkyl.

The term “oxy derivative”, as used herein, is defined as including—O—R<11> groups wherein R<11> is as defined above except for “oxyderivative”. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy,acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy,arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxysuch as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy,2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate. The term “thioderivative”, as used herein, is defined as including —S—R<11> groupswherein R<11> is as defined above except for “thio derivative”.Non-limiting examples are alkylthio, alkenylthio, alkynylthio andarylthio.

The term “amino derivative”, as used herein, is defined as including—NHR<11> or —NR<11>R<12> groups wherein R<11> and R<12> are as definedabove. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-and arylamino or mixed amino.

The term “acyl derivative”, as used herein, represents a radical derivedfrom carboxylic acid and thus is defined as including groups of theformula R<11>—CO—, wherein R<11> is as defined above and may also behydrogen. Preferred are acyl derivatives of formula —COR<11> whereinR<11> is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12alkenyl, heterocyle and aryl. Non-limiting examples are formyl, acetyl,propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl,cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl,furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl,oxamoyl.

The term “sulfonyl derivative”, as used herein, is defined as includinga group of the formula —SO—R<11>, wherein R<11> is as defined aboveexcept for “sulfonyl derivative”. Non-limiting examples arealkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

The term “sulfinyl derivative”, as used herein, is defined as includinga group of the formula —SO—R<11>, wherein R<11> is as defined aboveexcept for “sulfinyl derivative”. Non-limiting examples arealkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

The term “alkyl”, as used herein, is defined as including saturated,monovalent hydrocarbon radicals having straight, branched or cyclicmoieties or combinations thereof and generally containing 1-20 carbonatoms, most often 1 to 12 carbon atoms, preferably 1-7 carbon atoms fornon-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (in these twopreferred cases, unless otherwise specified, “lower alkyl”), eachoptionally substituted by, preferably 1 to 5, substituents independentlyselected from the group consisting of halogen, hydroxy, thiol, amino,nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinylderivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl,sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester,oxyamido, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy(preferably C6-10) and aryl(preferably C6-10).

In some embodiments are alkyl groups containing 1 to 7 carbon atoms,each optionally substituted by one or more substituents selected fromhydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio,cyclopropyl, acyl and phenyl. Most preferred are C1-4 alkyl and C3-7cycloalkyl, each optionally substituted by one or more hydroxy, halogen,lower alkyl or/and azido.

In some embodiments are alkyl groups are hydroxymethyl, propyl, butyl,2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl,2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

The term “lower alkyl”, as used herein, and unless otherwise specified,refers to C1 to C7 saturated straight, branched or cyclic hydrocarbon.Non limiting examples are methyl, ethyl, propyl, isopropyl, butyl,tertiobutyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl,hexyl, isohexyl, cyclohexyl, 3-methypentyl, 2,2-dimethylbutyl,optionally substituted with any suitable group, including but notlimited to one or more moieties selected from groups as described abovefor the alkyl groups. Preferably, lower alkyl is methyl.

The term “alkenyl”, as used herein, is defined as including bothbranched and unbranched, unsaturated hydrocarbon radicals having atleast one double bond, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro,cyano, aryl and heterocycle.

In some embodiments are alkenyl groups are C2-C12 alkenyls, especiallyC2-6alkenyls, such as ethenyl (=vinyl), 1-methyl-1-ethenyl,2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl,2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl,3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl and the like, optionally beingsubstituted by one or more substituents selected from halogen, cyano,thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl. Mostpreferred is vinyl, optionally substituted by one or more halogen or/andlower alkyl, and especially 2,2-difluorovinyl, 2,2-dibromovinyl and2,2-dichlorovinyl.

The term “alkynyl” as used herein, is defined as including a monovalentbranched or unbranched hydrocarbon radical containing at least onecarbon-carbon triple bond, for example ethynyl, 2-propynyl (=propargyl),and the like, and being optionally substituted by at least onesubstituent selected from the group consisting of halogen, hydroxy,thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido,alkylthio, alkyl and acyl.

In some embodiments are alkynyl groups are C2-12 alkynyl, especiallyC2-6 alkynyl, optionally being substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, acyl, arylsuch as phenyl and alkyl, preferably cycloalkyl.

In some embodiments are ethynyl, propynyl and butynyl, optionallysubstituted by lower alkyl or/and halogen, and especially 1-propynyl,cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl representstraight- or branched chains, C1-12, preferably C1-4-alkylene or C2-12-,preferably C2-4-alkenylene or -alkynylene moieties respectively.

Groups where branched derivatives are conventionally qualified byprefixes such as “n”, “sec”, “iso” and the like (e.g. “n-propyl”,“sec-butyl”) are in the n-form unless otherwise stated.

The term “aryl”, as used herein, is defined as including an organicradical derived from an aromatic hydrocarbon consisting of at least onering, most often 1 to 3 rings and generally containing 6-30 carbon atomsby removal of one hydrogen, such as phenyl and naphthyl, each optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl,sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonicacid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio,oxyester, oxyamido, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl,C1-6-haloalkyl. Aryl radicals are preferably monocyclic or bicycliccontaining 6-10 carbon atoms. Preferred aryl groups are phenyl andnaphthyl each optionally substituted by one or more substituentsindependently selected from halogen, nitro, amino, azido, C1-6-alkoxy,C1-6-alkyl, C1-6-haloalkyl, sulfonyl and phenyl.

In some embodiments the aryl is phenyl, optionally substituted by one ormore halogen, lower alkyl, azido or nitro, such as 3-chlorophenyl and3-azidophenyl.

The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.

The term “hydroxy”, as used herein, represents a group of the formula—OH.

The term “thiol”, as used herein, represents a group of the formula —SH.

The term “cyano”, as used herein, represents a group of the formula —CN.

The term “nitro”, as used herein, represents a group of the formula—NO2.

The term “nitrooxy”, as used herein, represents a group of the formula—ONO2.

The term “amino”, as used herein, represents a group of the formula—NH2.

The term “azido”, as used herein, represents a group of the formula —N3.

The term “carboxy”, as used herein, represents a group of the formula—COOH.

The term “sulfonic acid”, as used herein, represents a group of theformula —SO3H.

The term “sulfonamide”, as used herein, represents a group of theformula —SO2NH2.

The term “ester”, as used herein, is defined as including a group offormula —COO—R<11> wherein R<11> is as defined above except oxyderivative, thio derivative or amino derivative. Preferred are esters offormula —COOR<11> wherein R<11> is selected from C1-12 alkyl, C2-12alkenyl, C2-12 alkynyl and aryl. Most preferred are esters where R<11>is a lower alkyl, especially methyl.

The term “ether” is defined as including a group selected fromC1-50-straight or branched alkyl, or C2-50-straight or branched alkenylor alkynyl groups or a combination of the same, interrupted by one ormore oxygen atoms.

The term “amido” is defined as including a group of formula —CONH2 or—CONHR<11> or —CONR<11>R<12> wherein R<11> rand R<12> are as definedabove.

The term “heterocycle”, as used herein, is defined as including anaromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety asdefined above, having at least one O, S and/or N atom interrupting thecarbocyclic ring structure and optionally, one of the carbon of thecarbocyclic ring structure may be replaced by a carbonyl, and optionallybeing substituted with any suitable group, including but not limited toone or more moieties selected from lower alkyl, or other groups asdescribed above for the alkyl groups. Non-limiting examples ofheterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl,triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl,quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl,indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl,1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl,benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl,benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl,1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenothiazinyl, furazanyl, benzodioxolyl, isochromanyl,indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl,morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl,2-oxo-pyrrolidinyl, sugar moieties (i.e. glucose, pentose, hexose,ribose, fructose, which may also be substituted) optionally substitutedby alkyl or as described above for the alkyl groups. The term“heterocycle” also includes bicyclic, tricyclic and tetracyclic, spirogroups in which any of the above heterocyclic rings is fused to one ortwo rings independently selected from an aryl ring, a cyclohexane ring,a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or anothermonocyclic heterocyclic ring or where a monocyclic heterocyclic group isbridged by an alkylene group, such as quinuclidinyl,7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl,8-azabicyclo(3.2.1)octanyl.

The heterocycle may be selected from triazolyl, tetrazolyl,pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl,furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyland piperazinyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino,acyl and phenyl. In some embodiments the heterocycle is selected fromtetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl andthienyl, each optionally substituted by one or more substituentsselected from halogen, alkyl, halogen substituted alkyl, acyl, alkoxy,nitro, amino and phenyl, and especially from 2- and 3-thienyl,optionally substituted by one or more halogen, acyl such as formyl,cyano and/or lower alkyl, such as methyl.

In the above definitions it is to be understood that when a substituentsuch as R<1>, R<2>, R<3>, R<4>, R<5>, R<7>, R<8>, R<9>, R<10> isattached to the rest of the molecule via a heteroatom or a carbonyl, astraight- or branched chain, C1-12-, preferably C1-4-alkylene or C2-12,preferably C2-4-alkenylene or -alkynylene bridge may optionally beinterposed between the heteroatom or the carbonyl and the point ofattachment to the rest of the molecule.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating said free base formwith an appropriate acid such as an inorganic acid, for example, ahydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric,phosphoric and the like; or an organic acid, such as, for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic,maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt form,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula I and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula I and some of their intermediates haveat least one stereogenic center in their structure. This stereogeniccenter may be present in a R or a S configuration, said R and S notationis used in correspondence with the rules described in Pure Appl. Chem.(1976), 45, 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula Ior mixtures thereof (including all possible mixtures of stereoisomers).

Furthermore, certain compounds of formula I which contain alkenyl groupsmay exist as Z (zusammen) or E (entgegen) isomers. In each instance, theinvention includes both mixture and separate individual isomers.

Multiple substituents on the piperidinyl or the azepanyl ring can alsostand in either cis or trans relationship to each other with respect tothe plane of the piperidinyl or the azepanyl ring.

Some of the compounds of formula I may also exist in tautomeric forms.Such forms although not explicitly indicated in the above formula areintended to be included within the scope of the present invention.

With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof unless the particular isomeric formis referred to specifically.

The invention also includes within its scope prodrug forms of thecompounds of formula I and Its various sub-scopes and sub-groups.

The term “prodrug” as used herein includes compound forms which arerapidly transformed in vivo to the parent compound according to theinvention, for example, by hydrolysis in blood. Prodrugs are compoundsbearing groups which are modified by biotransformation prior toexhibiting their pharmacological action. Such groups include moietieswhich are readily oxidised, cyclised or cleaved, which compound afterbiotransformation remains or becomes pharmacologically active. Forexample, metabolically cleavable groups form a class of groups wellknown to practitioners of the art. They include, but are not limited tosuch groups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like),unsubstituted and substituted carbocyclic aroyl (such as benzoyl,substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such asethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethylsilyl),monoesters formed with dicarboxylic acids (such as succinyl), phosphate,sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compoundsbearing the biotransformable groups have the advantage that they mayexhibit improved bioavailability as a result of enhanced solubilityand/or rate of absorption conferred upon the parent compound by virtueof the presence of the biotransformable group. T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery System”, Vol. 14 of the A.C.S. SymposiumSeries; “Bioreversible Carriers in Drug Design”, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987.

The term “R substituent” refers to R<1>, R<2>, R<3>, R<4> or R<5>,independently.

According to one embodiment, the present invention relates to a compoundof formula I as defined above wherein n represents 0. The compound is a6-ring structure (2-thioxo- or 2-oxo-piperidinyl derivative) whereinR<1> is not existent since n=0, and is depicted by the formula (I-A).

According to a following embodiment, the present invention relates to acompound of formula I according to the invention as defined abovewherein n represents 1. The compound is a 7-ring structure (2-thioxo- or2-oxo-azepanyl derivative) wherein R<1> is existent since n=1 anddepicted by the formula (I-B).

According to one embodiment, the invention relates to said compound asdefined above wherein n=0, R<3> and/or R<4> are different from hydrogenand R<2> and R<5> represent hydrogen.

According to another embodiment, the invention relates to said compoundas defined above wherein n=1, R<2>, R<3> and/or R<4> are different fromhydrogen and wherein R<1> and R<5> represent hydrogen.

According to another embodiment, the invention relates to said compoundas defined above wherein only one R substituent chosen from R<3> or R<4>when n=0 or from R<2>, R<3> or R<4> when n=1, is different from hydrogenand the remaining R substituent(s) is/are hydrogen. We hereby refer to amono-substituted 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo- or2-oxo-azepanyl derivatives. According to another embodiment, the presentinvention relates to compounds of formula I according to the inventionas defined above wherein A<1> represents an oxygen atom. We hereby referto 2-oxo-piperidinyl or 2-oxo-azepanyl derivatives.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein X is CONR<7>R<8>, especially CONH2. We hereby refer to amidoderivatives of 2-oxo(or thioxo)-piperidinyl or 2-oxo(orthioxo)-azepanyl.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein R<6> represents hydrogen, C1-4 alkyl, or a CH2-R<6a> groupwherein R<6a> represents a heterocycle. Most preferably R<6> is a C1-4alkyl, especially ethyl. When R<6> is ethyl we refer to 2-(2-oxo(orthioxo)-1-piperidinyl)butanamide or 2-(2-oxo(orthioxo)-1-azepanyl)butanamide derivatives.

According to another embodiment, the present invention relates tocompounds of formula I according to the invention as defined abovewherein the carbon atom to which R<6> is attached is of the Sconfiguration. In case where R<6> is ethyl, A is oxygen and X is CONR<7>R<8>, we refer then to (2S)-2-(2-oxo-1-piperidinyl)butanamide or(2S)-2-(2-oxo-1-azepanyl)butanamide derivatives.

According to one embodiment, the present invention relates to a compoundas defined above wherein R<2> when n=1, R<3> and R<4> are the same ordifferent and each is independently hydrogen, halogen, nitro, nitrooxy,cyano, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl,alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonylderivative or sulfinyl derivative: R<1> when existent, R<2> when n=0 andR<5> are hydrogen; R<6> is hydrogen, alkyl, aryl or —CH2-R<6a> whereinR<6a> is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;provided that, when R<6> is hydrogen, X is —CONR<7>R<8> and that thecompound is neither methyl(2R)-2-[(6R)-6-methyl-2-oxoazepanyl]-3-phenylpropanoate nor methyl(2S)-2-[(4R)-4-methyl-2-oxoazepanyl]-3-phenylpropanoate.

According to this embodiment, the compound is generally such that whenR<6> is benzyl, X is —COOCH3 and n=1, R<2> is different from methyl whenR<3> and

R<4> are both hydrogen and R<4> is different from methyl when R<2> andR<3> are both hydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein R<2> when n=1, R<3> and R<4> are thesame or different and each is independently hydrogen; cyano; carboxy;amido;

C1-12 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cycloalkyl, acyl, aryl and heterocycle;C2-12 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl;C2-12 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryland acyl; acyl derivative of formula —CO—R<11>, wherein R<11> isselected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl;ester of formula —CO—O—R<11> wherein R<11> is selected from C1-12 alkyl,C2-12 alkenyl, C2-12 alkynyl and aryl;heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl,1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl,each optionally substituted by one or more substituents selected fromhalogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl andphenyl;aryl, each optionally substituted by one or more substituents selectedfrom C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino,azido, sulfonyl, aryl and nitro.

According to another embodiment, the present invention relates to acompound as defined above, wherein R<2> when n=1, R<3> and R<4> are thesame or different and each is independently hydrogen;

C1-7 alkyl, each optionally substituted by one or more substituentsselected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido,alkyltio, cyclopropyl, acyl and phenyl;C2-6 alkenyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl:C2-6 alkynyl, each optionally substituted by one or more substituentsselected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl,phenyl and acyl: heterocycle selected from tetrazolyl, pyrrolidinyl,pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionallysubstituted by one or more substituents selected from halogen, alkyl,halogen substituted alkyl, acyl, alkoxy, nitro, amino and phenyl;phenyl, each optionally substitued by one or more substituents selectedfrom C1-6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino,azido, sulfonyl, phenyl and nitro.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently C1-4-alkyl orC3-7-cycloalkyl, optionally substituted by one or more halogen, hydroxy,lower alkyl and/or azido.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently vinyl, optionallysubstituted by one or more halogen or/and lower alkyl.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the group R3and R<4> when n=0, represents independently ethynyl, propynyl orbutynyl, optionally substituted by one or more halogen and/or loweralkyl.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently phenyl, optionallysubstituted by one or more halogen, lower alkyl, azido and/or nitro.

According to another embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<2>, R<3> and R<4> when n=1 or from the groupR<3> and R<4> when n=0, represents independently 2- or 3-thienyl,optionally substituted by one or more halogen, acyl, cyano or/and loweralkyl.

According to a particular embodiment, the present invention relates to acompound as defined above wherein at least one of the R substituentschosen from the group R<3>, R<4> and R<2> when n=1 or from the groupR<3> and R<4> when n=0, is hydroxymethyl, propyl, butyl,3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl,iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl,3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl,2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl,3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl,1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl,2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl,2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to yet another embodiment, the present invention relates to acompound as defined above wherein R<1>, R<2>, R<4> and R<5> arehydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein R<1>, R<2>, R<3> and R<5> arehydrogen.

According to another embodiment, the present invention relates to acompound as defined above wherein n=1 and R<1>, R<3>, R<4> and R<5> arehydrogen.

In all the above-mentioned scopes when the carbon atom to which R<6> isattached is asymmetric it may be in the “S”-configuration.

Representative compounds of this invention as defined above are selectedfrom the group consisting of2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-propyl-1-piperidinyl)butanamide,2-12-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo 1-piperidinyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-propyl-1-piperidinyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoroproyl)-1-piperidinyl]butanamide,2-14-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(iodomethyl)-2-oxo-1-piperldinyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,2-12-oxo-4-(2-thienyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide,2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide,2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-14-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide,2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-propyl-1-azepanyl)butanamide,2-[2-oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-(5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-5-phenyl-1-azepanyl)butanamide,2-[2-oxo-5-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide,2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-[5-ethynyl-2-oxo-1-azepanyl]butanamide,2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-5-(1-propynyl)-1-azepanyl]butanamide,2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-propyl-1-azepanyl)butanamide,2-[2-oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-16-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-6-phenyl-1-azepanyl)butanamide,2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide,2-[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(6-ethynyl-2-oxo-1-azepanyl)butanamide,2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[6-(4-methyl-2-thienyl]-2-oxo-1-azepanyl]butanamide,2-[2-oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-6-(1-propynyl)-1-azepanyl]butanamide,2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-propyl-1-azepanyl)butanamide,2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,2-14-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,2-f4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,2-(2-oxo-4-phenyl-1-azepanyl)butanamide,2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,2[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[<4>-(5-cyano-<2>-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide,2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(1-butynyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2-chloro-2,2-difluoroethyl]-2-oxo-1-azepanyl]butanamide,2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

Results have been obtained with the following compounds:

-   (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-(2-oxo-5-phenyl-1-piperidinyl]butanamide,-   (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,-   2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xv) International Patent Application Publication No. WO2008/132139

In some embodiments, the compounds are of formula (I) as follows:

whereinY is O or S. In some embodiments Y is O. R1 is hydrogen or C-|.g alkyl;R2 is hydrogen;R3 is —CONR5R6, —COR7, an imidazolyl, an imidazopyridinyl, animidazopyridazinyl; R5, R6 are the same or different and areindependently selected from hydrogen and C-|_(—)6 alkyl;R7 is C<;|_(—)6 alkyl;

A is a monocyclic or bicyclic heterocyclic moiety selected from thegroup consisting of imidazolidin-1-yl, 1,3-oxazolidin-3-yl,2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol-3(2H)-yl, 1,3-thiazolidin-3-yl,piperidin-1-yl, azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl,hexahydro-4H-thieno[3,2-b]pyrrol-4-yl,2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl,1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl,3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H)-yl,1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl; R4 is either R̂a or R̂b dependingon whether A being is a monocyclic or a bicyclic heterocycle:

where A is a monocyclic heterocyclic moiety, R̂ is R̂a which is selectedfrom the group consisting of hydrogen; C-|.g alkyl optionallysubstituted by a substituent selected from halogen, C-1.4 alkoxy, C-1.4alkylthio, azido, nitrooxy or an aryl; C2-6 alkenyl optionallysubstituted by halogen; C2-6 alkynyl optionally substituted by halogen;azido; alkoxycarbonylamino; arylsulfonyloxy; a substituted orunsubstituted aryl; or a 3-8 membered substituted or unsubstitutedheterocycle; where A is a bicyclic heterocyclic moiety R̂ is R̂ which isselected from the group comprising or consisting of hydrogen; nitro;cyano; halogen; heterocycle; amino; aryl; C-|.g alkyl optionallysubstituted by at least one halogen; or C-|.g alkoxy optionallysubstituted by at least one halogen; In some embodiments the compoundsare as follows:

For compounds where A=Y is selected from a 2-oxo-piperidin-1-yl, a2-oxo-azepan-1-yl, a 2-oxo-1,3-benzothiazol-3(2H)-yl or a2-oxo-1,3-benzoxazol-3(2H)-yl, R3 must be selected from an imidazolyl,an imidazopyridinyl or an imidazopyridazinyl.

For compounds where A=Y is a 5-oxoimidazolidin-1-yl, R̂ and R̂ arehydrogen, R3 is —CONR5R6, R5 anc|R6 are as above defined, then R̂a maynot be an alkyl, aralkyl or substituted aralkyl.

Where A=Y is either of a 2-oxo-piperidin-1-yl and a 2-oxo-azepan-1-yl,R̂, R̂ and R̂a are all hydrogen, then R̂ could not be a2-phenylimidazo[1,2-a]pyridin-3-yl.

In a specific embodiment A=Y is selected from the list consisting of:

wherein X is O or S, in a more specific embodiment O; in anotherembodiment, X is S.

The asterisks in the above illustration indicate the attachment sites ofthe substituent R̂a.

In a specific embodiment, when R̂ is —CONR5R6 and R̂ is C-μg alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

In a specific embodiment R̂ is hydrogen, methyl, ethyl and R̂ is hydrogen.In a specific embodiment R3 is —CONH2.

In a further specific embodiment R̂ is 1H-imidazol-1-yl,1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. In a specific embodiment R̂a is a C-|.galkyl which may optionally be substituted by a halogen; or a phenyl.

In another specific embodiment R̂b is hydrogen, halogen, nitro, cyano ora C-μg alkyl optionally substituted by a halogen.

In still a further embodiment compounds may be used in the treatment ofthe above mentioned disorders, in particular of epilepsy, having theformula (I-E), as wells as its geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

wherein

X is O or S;

R-I is hydrogen or C-|.g alkyl, in a more specific embodiment hydrogen;R3 is an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl; R̂b ishydrogen; nitro; cyano; halogen; C-|.g alkyl optionally substituted byhalogen; C-|.g alkoxy optionally substituted by halogen.

A further aspect of the present invention consists in novel compoundshaving the formula (I-A), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

whereinR1 is hydrogen or C-|.g alkyl, preferably hydrogen, methyl or ethyl; ina more specific embodiment R̂ is ethyl.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl,preferably R̂ is —CONH2.

R̂a is either hydrogen or an aryl; with the proviso that2-(5-oxoimidazolidin-1-yl)acetamide is excluded. Preferably R̂a is anaryl, e.g. a phenyl which may be substituted preferably by halogen,nitro, alkoxy, in particular by nitro.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in novel compoundshaving the formula (I-B1 or I-B2), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

wherein X in formula (I-B2) is either S or O, in a more specificembodiment S;

R1 is hydrogen or C-|.g alkyl, preferably hydrogen, methyl or ethyl; ina more specific embodiment R̂ is ethyl.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;preferably R̂ is —CONH2R̂a is hydrogen; C-|.g alkyl optionally substituted by halogen or C-1.4alkoxy; an aryl; or C2.g alkenyl optionally substituted by halogen.Preferably, R̂a is C-|.g alkyl optionally substituted by halogen or C2-6alkenyl optionally substituted by halogen or an aryl. In a more specificembodiment R̂a is C-|.g alkyl optionally substituted by halogen or aryl.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in novel compoundshaving the formula (I-B3), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

whereinR1 is either hydrogen or C-μg alkyl, preferably hydrogen, methyl orethyl; more preferably R1 is ethyl.R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;preferably R̂ is —CONH2 R̂a is C-|_(—)5 alkyl optionally substituted byhalogen or C-1.4 alkoxy; an aryl; or C2_g alkenyl optionally substitutedby halogen.

Preferably, R̂a is C-|.g alkyl optionally substituted by halogen or C2_galkenyl optionally substituted by halogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration. A further aspect of the present invention consists innovel compounds having the formula (I-C), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR1 is hydrogen or C-|.g alkyl, in particular hydrogen, methyl or ethyl.R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;in particular R̂ is —CONH2R̂a is methyl, ethyl, butyl optionally substituted by halogen or C-1.4alkoxy, an unsubstituted phenyl or a phenyl substituted by halogen, aC-|.g alkyl optionally substituted by halogen or a C-1.4 alkoxy; or R̂ais a C2-6 alkenyl optionally substituted by halogen. Preferably, R̂a ismethyl, optionally substituted by halogen, an unsubstituted phenyl or aphenyl substituted by halogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and Rβ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingthe formula (I-D1 or I-D2), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

whereinR-I is hydrogen or C-|.g alkyl, in particular hydrogen; R3 is animidazolyl, an imidazopyridinyl or an imidazopyridazinyl. In oneembodiment, R̂ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl. In a morespecific embodiment, R̂ is 1H-imidazol-1-yl, 1H-imidazol-4-yl,1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl; R̂a is hydrogen, C-|.galkyl optionally substituted by halogen or C-1.4 alkoxy; aryl; or C2-galkenyl optionally substituted by halogen. In a specific embodiment, R̂ais C-|.g alkyl optionally substituted by halogen; aryl; or C2-6 alkenyloptionally substituted by halogen. In a more specific embodiment R̂a isC-|.g alkyl optionally substituted by halogen; or aryl; e.g, propyl orphenyl; with the proviso that when R̂ and R̂a are hydrogen, R̂ is not2-phenylimidazo[1,2-a]pyridin-3-yl.

A further aspect of the present invention consists in compounds havingthe formula (I-F1, I-F2 or I-F3), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR-I is hydrogen or C-|.g alkyl, preferably hydrogen, methyl or ethyl;more preferably, R̂ is hydrogen.

R3 is —CONH2, an imidazolyl, an imidazopyridinyl or animidazopyridazinyl; in a more specific embodiment R3 is —CONH2,1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl.

R̂b is hydrogen; halogen; nitro; cyano; C1.4 alkyl optionally substitutedby halogen; C-1.4 alkoxy optionally substituted by halogen. In a morespecific embodiment R̂ is hydrogen, halogen or cyano, more specificallyhalogen.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R1 and Rβ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingthe formula (I-F4), their geometrical isomers, enantiomers,diastereomers and mixtures, or a pharmaceutically acceptable saltthereof,

whereinR-I is hydrogen or C-|.g alkyl, preferably hydrogen;R3 is an imidazolyl, an imidazopyridinyl or an imidazopyridazinyl; morespecifically R̂ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl,imidazo[1,2-a]pyridin-3-yl or imidazo[1,2-b]pyridazin-3-yl. MorespecificallyR̂ is 1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl.R̂b is hydrogen; halogen; nitro; cyano; C-1.4 alkyl optionallysubstituted by halogen; C-1.4 alkoxy optionally substituted by halogen;specifically R̂ is hydrogen, halogen or cyano.

In a particular embodiment, when R̂ is —CONH2 and R̂ is C-|.g alkyl, thecarbon atom to which R-I and R̂ are attached is preferably in the“S”-configuration.

A further aspect of the present invention consists in compounds havingeither of the formula (I-G1, I-G2 or I-G3), their geometrical isomers,enantiomers, diastereomers and mixtures, or a pharmaceuticallyacceptable salt thereof,

whereinR-I is hydrogen or C-|.g alkyl; preferably hydrogen;R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl;in a more specific embodiment R̂ is —CONH2, 1H-imidazol-1-yl,1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl orimidazo[1,2-b]pyridazin-3-yl. In a even more specific embodiment R3 isan 1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl;R4D js hydrogen; halogen; C-1.4 alkyl optionally substituted by halogen;C-1.4 alkoxy optionally substituted by halogen.

Specific compounds of the present invention are those selected from thegroup consisting of:(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(25)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one;1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one;5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one;1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one;4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one;1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;2-(6-chloro-2-0X0-1,3-benzothiazol-3(2H)-yl)acetamide;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one;1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one;2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide;5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one;2-(6-iodo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one;and7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

In some embodiments, compounds of the present invention are thoseselected from the group consisting of:1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; and5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“C-|₁₃β alkyl” refers to alkyl groups having 1 to 6, or 1 to 4 carbonatoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,trifluoromethyl and the like. “Aryl” refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferredaryl include phenyl, naphthyl, phenantrenyl and the like.

“Heterocycle” refers to a saturated or unsaturated ring systemcontaining, in addition to carbon atoms, at least one hetero atom, suchas nitrogen, oxygen and/or sulfur. “Heterocycle” includes both“heteroaryl” and “heterocycloalkyl”.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazopyridinyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl, benzoquinolyl, imidazopyrimidinyl, imidazopyridazinyl,imidazothiazolyl or imidazothiadiazolyl.

“C2-6 alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Preferable alkenyl groups include ethenyl (vinyl, —CH═CH2), n-2-propenyl(allyl, —CH2CH═CH2) and the like.

“C2-6 alkynyl” refers to alkynyl groups preferably having from 2 to 6carbon atoms and having at least 1-2 sites of alkynyl unsaturation,preferred alkynyl groups include ethynyl (—C≡CH), propargyl (—CH2C≡CH),and the like.

“C3.8 cycloalkyl” refers to a saturated carbocyclic group of from 3 to 8carbon atoms having a single ring (e.g., cyclohexyl) or multiplecondensed rings (e.g., norbornyl). Preferred cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and thelike.

“Heterocycloalkyl” refers to a C3.8 cycloalkyl group according to thedefinition above, in which 1 to 3 carbon atoms are replaced by heteroatoms chosen from the group consisting of O, S, NR, R being defined ashydrogen or C-|.g alkyl.

“Alkoxy” refers to the group —O—R where R includes “C-μg alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”,“heteroaryl”.

“Amino” refers to the group —NRR′ where each R, R′ is independentlyhydrogen, “C-|.g alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3-8cycloalkyl”,

“heterocycloalkyl”, “aryl”, “heteroaryl”, and where R and R′, togetherwith the nitrogen atom to which they are attached, can optionally form a3-8-membered heterocycloalkyl ring.

“Amido” refers to the group —C(═O)NRR′ where each R, R′ is independentlyhydrogen, “C-|_(—)5 alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3.8cycloalkyl”, “heterocycloalkyl”, “aryl”,

“heteroaryl”, and where R and R′, together with the nitrogen atom towhich they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“Acylamino” refers to the group —NRC(O)R′ wherein R and R′ are asdefined hereabove for the amino group.

“Ureido” refers to the group —NR″C(O)NRR′ wherein R and R′ are asdefined hereabove for the amino group, and R¹¹ is as defined hereabove.“Sulfanyl” refers to the group —SR where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfinyl” refers to the group —S(═O)R where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Sulfonyl” refers to the group —S(═O)2R where R is “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl”, “aryl”or “heteroaryl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “alkenyl”, “alkynyl”, “aryl” and

“heteroaryl” etc. groups can optionally be substituted with from 1 to 5substituents selected from the group consisting of “C-|.g alkyl”, “C2-6alkenyl”, “C2-6 alkynyl”,

“cycloalkyl”, “heterocycloalkyl”, “amino”, “amido”, “acylamino”,“ureido”, “aryl”, “heteroaryl”, “alkoxy”, “halogen”, cyano, hydroxy,mercapto, nitro, “amido”, “sulfanyl”, “sulfinyl”, “sulfonyl” and thelike.

The acid addition salt form of a compound of formula (I) that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic,succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active, non-toxic base addition salt forms,e.g. metal or amine salts, by treatment with appropriate organic andinorganic bases. Appropriate base salt forms include, for example,ammonium salts, alkali and earth alkaline metal salts, e.g. lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms bytreatment with an appropriate base or acid.

Compounds of the formula (I) and their salts can be in the form of asolvate, which is included within the scope of the present invention.Such solvates include for example hydrates, alcoholates and the like.

Many of the compounds of formula (I) and some of their intermediateshave at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem., 45 (1976) 11-30.

The invention also relates to all stereoisomeric forms such asenantiomeric and diastereoisomeric forms of the compounds of formula (I)or mixtures thereof (including all possible mixtures of stereoisomers).With respect to the present invention reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof, unless the particular isomeric formis referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

Some of the compounds of formula (I) may also exist in tautomeric forms.Such forms although not explicity indicated in the above formula areintended to be included within the scope of the present invention.

The invention also includes within its scope pro-drug forms of thecompounds of formula (I) and its various sub-scopes and sub-groups.

In a specific embodiment, the present invention concerns a compoundselected from the group consisting of:(2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide;(2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide;2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide;2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide;(+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide;(2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)propanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide;2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide;2-(2-oxo-5-propyl-1,3-thiazolidin-3-yl)propanamide;(2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one;1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-5-ylmethyl)-4-propylpiperidin-2-one;1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one;1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2-one;5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-5-phenylazepan-2-one;5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one;1-(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one;1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one;4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one;4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one;1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(2-OXO-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one;6-bromo-3-(2-oxopropyl)-1,3-benzothiazol-2(3H)-one;2-(6-nitro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide;2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide;6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3-benzoxazol-2(3H)-one;1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one;2-(6-chloro-3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanamide;5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one;2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-bromo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide;1-(1H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1H)-one;2-(6-iodo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide;7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one;7-chloro-3-(1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one;and7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

xvi) UK Patent 1,039,113

The new compounds according to the present invention are N-substitutedlactams of the general formula:

wherein N is a whole number of from 3 to 5 and R represents a

radical in which m is 0, 1 or 2 and R′ is a hydrogen atom or an alkyl,cycloalkyl, alkenyl or alkynyl radical, which may contain 3 to 6 carbonatoms, or an aryl radical, and R¹¹ is a hydrogen atom or an alkylradical, or both R′ and R″, together with the nitrogen atom to whichthey are attached, form a heterocyclic ring, such as 5 a pyrrolidinering.

xvii) UK Patent 1,309,692

According to the present invention, there are provided new N-substitutedlactams of the general formula:

wherein X is a hydrogen atom or an alkyl, alkenyl or alkynyl radicalcontaining 1 to 6 carbon atoms, p is a whole number of from 1 to 6, Y isa hydrogen atom or an alkyl, alkenyl or alkynyl radical containing 1 to6 carbon atoms or a cycloalkyl radical and R′ and R″, which may be thesame or different, are hydrogen atoms or alkyl, alkenyl, alkynyl,cycloalkyl or aryl radicals or R′ and R″, together with the nitrogenatom to which they are attached, form a heterocyclic radical which maycontain further heteroatoms, with the proviso that at least one of thesymbols X and Y is other than a hydrogen atom.

Valproate

In some embodiments, an SV2A inhibitor or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug is administeredin combination with valproate or its analog, derivative orpharmaceutically acceptable salt, hydrate, solvate, or polymorph orprodrug.

Analogs and derivatives of valproate useful for the methods andcompositions of this invention include compounds of the formula:

wherein, independently for each occurrence:

X is —OH, C₁₋₁₀ alkoxy, —O-alkali metal, —N(R¹)₂, —SH, or —S—C₁₋₁₀alkyl;

R is a straight chain or branched C₁₋₃₀ alkyl; and

R¹ is H, C₁₋₁₀ alky, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, or aralkyl;

provided that R may be unsubstituted or substituted by one or more —OH,C₁₋₁₀ alkoxy, —N(R¹)₂, —SH, —S—C₁₋₁₀ alkyl, or aryl.

In other embodiments, analogs and derivatives of valproate useful forthe methods and compositions of this invention include compounds of theformula:

-   -   wherein, independently for each occurrence:    -   X is —OH, C₁₋₁₀ alkoxy, —O-alkali metal, —N(R¹)₂, —SH, or        —S—C₁₋₁₀ alkyl;    -   R is CH[(CH₂)₂CH₃]₂; and    -   R¹ is H, C₁₋₁₀ alky, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, or        aralkyl;

provided that R may be unsubstituted or substituted by one or more —OH,C₁₋₁₀ alkoxy, —N(R¹)₂, —SH, —S—C₁₋₁₀ alkyl, or aryl.

In other embodiments, analogs and derivatives of valproate useful forthe methods and compositions of this invention include compounds of theformula:

-   -   wherein, independently for each occurrence:    -   X is —OH, —O-alkali metal, —SH, or —NH₂; and    -   R is CH[(CH₂)₂CH₃]₂.

Methods for making the compounds of formula may be found in, forexample, U.S. Pat. Nos. 4,558,070; 4,595,695; 4,654,370; 4,895,873;4,913,906; 5,017,613; 5,019,398; 5,049,586; 5,162,573; 5,440,023;5,856,569; 6,131,106 and 6,610,326.

Other names and descriptions of valproate are also envisioned herein,such as Depakote, Valrelease, 2-propylpentanoate, valproic acid, VPA andsodium valproate.

Methods of Treating Cognitive Impairment Associated with CNS Disorderswith the Administration of an SV2A Inhibitor

In one aspect, the invention provides methods and compositions fortreating cognitive impairment or improving cognitive function, delayingor slowing the progression of cognitive impairment, or reducing the rateof decline of cognitive function, in a subject suffering from cognitiveimpairment associated with a central nervous system (CNS) disorder(e.g., age-related cognitive impairment, MCI, amnestic MCI, dementia,AD, prodromal AD, PTSD, schizophrenia, ALS and cancer therapy-relatedcognitive impairment), or the risk thereof in a subject in need thereofby administering an SV2A inhibitor or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof. In someembodiments, the SV2A inhibitor is administered in combination withvalproate or an analog, derivative or pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof. In some embodiments,the SV2A inhibitor is selected from the group consisting oflevetiracetam, seletracetam, and brivaracetam or derivatives or analogsor pharmaceutically acceptable salts, or solvates, or hydrates, orpolymorphs, or prodrugs thereof. In other embodiments, the SV2Ainhibitor is levetiracetam or a derivative or an analog or apharmaceutically acceptable salt, or a solvate, or a hydrate, or apolymorph, or a prodrug thereof. In other embodiments, the SV2Ainhibitor is brivaracetam or a derivative or an analog or apharmaceutically acceptable salt, or a solvate, or a hydrate, or apolymorph, or a prodrug thereof. In other embodiments, the SV2Ainhibitor is seletracetam or a derivative or an analog or apharmaceutically acceptable salt, or a solvate, or a hydrate, or apolymorph, or a prodrug thereof. In some embodiments, the cognitiveimpairment is associated with age-related cognitive impairment, such asMild Cognitive Impairment (MCI), Age-Associated Memory Impairment(AAMI), Age Related Cognitive Decline (ARCD). In one embodiment of theinvention, the MCI is amnestic MCI. In some embodiments of theinvention, the cognitive impairment is associated with dementia,Alzheimer's Disease (AD), prodromal AD, post traumatic stress disorder(PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis,cancer-therapy-related cognitive impairment, mental retardation,Parkinson's disease, autism, compulsive. In one embodiment, the subjectthat suffers such cognitive impairment is a human patient. The subjectmay be a human or other mammal such as a non-human primate, or rodent(e.g., rat). In some embodiments, the subject is a human patient.

The use of the SV2A inhibitors and its pharmaceutically acceptable salt,hydrate, solvate or polymorph in combination with valproate or itsanalog, derivative or pharmaceutically acceptable salt reduces theamount of valproate necessary for the treatment of CNS disordersinvolving cognitive dysfunction and other affective disorders, includingMCI, amnestic MCI, AAMI, ARCE, dementia, AD, PTSD, schizophrenia,bipolar disorder, amyotrophic lateral sclerosis, cancer-therapy-relatedcognitive impairment, mental retardation, Parkinson's disease, autism,compulsive behavior, and substance addiction. In one embodiment, thesubject that suffers such cognitive impairment is a human patient, andthus the side effects caused by valproate is reduced without diminishingefficacy. Further, the efficacy of a combination of the SV2A inhibitoror its pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug and valproate or its analog, derivative, or pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof exceedsthe efficacy of either drug administered alone at its optimal dose andthus is an improved treatment for CNS disorders associated withcognitive impairment.

It will be appreciated that compounds and agents used in thecompositions and methods of this invention preferably should readilypenetrate the blood-brain barrier when peripherally administered.Compounds which cannot penetrate the blood-brain barrier, however, canstill be effectively administered directly into the central nervoussystem, e.g., by an intraventricular or other neuro-compatible route.

As used herein, administration of an SV2A inhibitor or itspharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug and valproate or its analog, derivative or pharmaceuticallyacceptable salt “in combination” includes simultaneous administrationand/or administration at different times, such as sequentialadministration. Simultaneous administration of the SV2A inhibitor or itspharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug and valproate or its analog, derivative or pharmaceuticallyacceptable salt can optionally be combined with supplemental doses ofthe SV2A inhibitor or its pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug and/or valproate or its analog,derivative or pharmaceutically acceptable salt. Simultaneousadministration of drugs encompasses administration as co-formulation or,alternatively, as separate compositions.

In accordance with this invention, the SV2A inhibitor or itspharmaceutically acceptable salt, hydrate, solvate or polymorph, aloneor in combination with valproate or its analog, derivative orpharmaceutically acceptable salt can be administered in an extendedrelease form, a controlled release form, a prolonged release form, asustained release form, a delayed release form, or a slow release form.

In accordance with this invention, the SV2A inhibitor or itspharmaceutically acceptable salt, hydrate, solvate or polymorph, aloneor in combination with valproate or its analog, derivative orpharmaceutically acceptable salt can be administered to a subject viaany suitable route or routes. In some embodiments, the drugs areadministered orally; however, administration intravenously,subcutaneously, intra-arterially, intramuscularly, intraspinally,rectally, intrathoracically, intraperitoneally, intracentricularly, ortransdermally, topically, or by inhalation is also contemplated. Theagents can be administered orally, for example, in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, or the like,prepared by art recognized procedures. In certain embodiments, the SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvate andpolymorphs, alone or in combination with valproate or its analog,derivative or pharmaceutically acceptable salt, can be administered to asubject via different routes. For example, the SV2A inhibitor its salt,solvate, hydrate, or polymorph is administered intravenously and thevalproate or an analog, derivative or pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered orally.

In some embodiments, the administration is a slow or extended release.The term “extended release” is widely recognized in the art ofpharmaceutical sciences and is used herein to refer to a controlledrelease of an active compound or agent from a dosage form to anenvironment over (throughout or during) an extended period of time, e.g.greater than or equal to one hour. An extended release dosage form willrelease drug at substantially constant rate over an extended period oftime or a substantially constant amount of drug will be releasedincrementally over an extended period of time. The term “extendedrelease” used herein includes the terms “controlled release,” “prolongedrelease,” “sustained release,” “delayed release,” or “slow release” asthese terms are used in the pharmaceutical sciences. In someembodiments, the extended release dosage is administered in the form ofa patch or a pump. The term “Extended release dosage form” or “extendedrelease form”, as used herein, refers to a dosage form that contains oneor more active ingredients, where the release of at least one of theactive ingredient, when placed in water or other biological fluids orsolvents, may occur over an extended period, such as a period of atleast about 1 day, at least about 2 days, at least about 3 days, atleast about 4 days, at least about 5 days, at least about 10 days, atleast about 20 days, at least about 30 days, at least about 60 days, atleast about 90 days, or at least about 150 days. In some embodiments ofthe present invention, only one of the SV2A inhibitor and valproate isin an extended release dosage form. In some other embodiments of thecomposition of the present invention, the SV2A inhibitor and valproateare each in an extended release dosage form (together in one formulationor separately in two formulations).

Dosage schedules of the agents and compositions according to the methodsof the invention will vary according to the particular compound orcompositions selected, the route of administration, the nature of thecondition being treated, the age, and condition of the patient, thecourse, or stage of treatment, and will ultimately be at the discretionof the attending physician. It will be understood that the amount of theSV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvateor polymorph, alone or in combination with valproate or its analog,derivative or pharmaceutically acceptable salt that is administered willbe amounts effective to produce a desired biological effect, such asbeneficial results, including clinical results, e.g., an amount thatnormalizes neural activity in areas of the brain that exhibit abberentactivity (including, but not limited to DG, CA3 and/or entorhinalcortex) and/or results in an improvement in cognitive function). It willbe understood that an effective amount can be administered in more thanone dose and over a course of treatment.

If administered by an implant, a device or a slow or extended releaseformulation, the SV2A inhibitor or its pharmaceutically acceptable salt,hydrate, solvate or polymorph, alone or in combination with valproate orits analog, derivative or pharmaceutically acceptable salt can beadministered one time, or one or more times periodically throughout thelifetime of the patient as necessary. Other administration intervalsintermediate to or shorter than these dosage intervals for clinicalapplications may also be used and may be determined by one skilled inthe art following the methods of this invention.

Desired duration of administration of the SV2A inhibitor or itspharmaceutically acceptable salt, hydrate, solvate or polymorph, aloneor in combination with valproate or its analog, derivative orpharmaceutically acceptable salt can be determined by routineexperimentation by one skilled in the art. For example, the SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvate orpolymorph, alone or in combination with valproate or its analog,derivative or pharmaceutically acceptable salt may be administered for aperiod of 1-4 weeks, 1-3 months, 3-6 months, 6-12 months, 1-2 years, ormore, up to the lifetime of the patient.

It is known in the art that normalization to body surface area is anappropriate method for extrapolating doses between species. The humanequivalent dose (HED) for this dosage can be estimated using thefollowing formula that accounts for differences in body surface area(see Estimating the Safe Starting Dose in Clinical Trials forTherapeutics in Adult Healthy Volunteers, December 2002, Center forBiologics Evaluation and Research):

HED=animal dose×(Km animal/Km human)

where the Km factor is body weight divided by body surface area (Km rathas been determined as 6, and Km human is 37; see Reagan-Saw, Nihal,Ahmad, 2007). Thus, a dosage of 10 mg/kg in rats is equivalent to 1.6mg/kg in humans (10 mg/kg×( 6/37)=1.6 mg/kg). For human subjects, tocalculate a dose in mg from the dose in mg/kg, the dose in mg/kg ismultiplied by a typical adult weight of 70 kg.

In certain embodiments of the invention, the dose of the SV2A inhibitoror its pharmaceutically acceptable salt, hydrate, solvate or polymorphis 0.1 to 5 mg/kg/day (which, given a typical human subject of 70 kg, is7 to 350 mg/day).

In certain embodiments of the invention, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof can be administered at doses according to, for example,U.S. patent application Ser. No. 12/580,464 (Pub. No. US-2010-0099735),U.S. patent application Ser. No. 13/287,531 (Pub. No. US-2012-0046336),U.S. patent application Ser. No. 13/370,253 (Pub. No. US-2012-0214859),International Patent Application PCT/US2009/005647 (Pub. No.WO2010/044878), International Patent Application PCT/US12/24556 (Pub.No. WO2012/109491), U.S. Patent Application 61/105,847, U.S. PatentApplication 61/152,631, U.S. Patent Application 61/175,536, and U.S.Patent Application 61/441,251. In certain embodiments of the invention,the SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is administered at a daily doseof about 0.001 to 5 mg/kg, about 0.001 to 0.5 mg/kg, about 0.01 to 0.5mg/kg, about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 2 to 4mg/kg, or about 2 to 3 mg/kg, or about 3 to 4 mg/kg, or about 0.2 to 0.4mg/kg, or about 0.2 to 0.3 mg/kg, or about 0.3 to 0.4 mg/kg, or about0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg,or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.5 to 2mg/kg, or about 0.8 to 1.6, or about 0.8 to 3.6, or about 0.5 to 4mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about0.05 to 3 mg/kg or about 0.08 to about 1.6 mg/kg, or about 0.08 to 3.6or about 0.05 to 2 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1mg/kg, or about 0.5 to 5 mg/kg, or about 0.05 to 0.5 mg/kg, or about 0.8mg/kg, or about 1.6 mg/kg, or about 3.6 mg/kg, or about 0.08 mg/kg, orabout 0.16 mg/kg, or about 0.36 mg/kg. Other doses higher than,intermediate to, or less than these doses may also be used and may bedetermined by one skilled in the art following the methods of thisinvention. For repeated administrations over several days or weeks orlonger, depending on the condition, the treatment is sustained until asufficient level of cognitive function is achieved.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.001-5 mg/kg/day (which, given a typical human subject of 70 kg, isabout 0.07-350 mg/day). Doses that may be used include, but are notlimited to 0.001 mg/kg/day, 0.0015 mg/kg/day, 0.002 mg/kg/day, 0.005mg/kg/day, 0.0075 mg/kg/day, 0.01 mg/kg/day, 0.015 mg/kg/day, 0.02mg/kg/day, 0.03 mg/kg/day, 0.04 mg/kg/day, 0.05 mg/kg/day, 0.1mg/kg/day, 0.2 mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day,0.75 mg/kg/day, 1.0 mg/kg/day, 1.5 mg/kg/day, 2.0 mg/kg/day, 2.5mg/kg/day, 3.0 mg/kg/day, 4.0 mg/kg/day, or 5.0 mg/kg/day. In someembodiments, the dose of the SV2A inhibitor is 0.001-0.5 mg/kg/day(which, given a typical human subject of 70 kg, is about 0.07-35mg/day), or 0.01-0.5 mg/kg/day (which is about 0.7-35 mg/day). Otherdoses higher than, intermediate to, or less than these doses may also beused and may be determined by one skilled in the art following themethods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.1 to 5 mg/kg/day (which, given a typical human subject of 70 kg, is7 to 350 mg/day). Doses that may be used include, but are not limited to0.1 mg/kg/day, 0.5 mg/kg/day, 1 mg/kg/day, 1.5 mg/kg/day, 2 mg/kg/day,2.5 mg/kg/day, 3 mg/kg/day, 4 mg/kg/day, or 5 mg/kg/day. In certainembodiments, the dose is 1-2 mg/kg/day (which, given a typical humansubject of 70 kg, is 70-140 mg/day). In other embodiments of theinvention, the dose of the SV2A inhibitor is 0.1 to 0.2 mg/kg/day. Otherdoses higher than, intermediate to, or less than these doses may also beused and may be determined by one skilled in the art following themethods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.01 to 2.5 mg/kg/day (which, given a typical human subject of 70 kg,is about 0.7-180 mg/day). Doses that may be used include, but are notlimited to 0.01 mg/kg/day, 0.02 mg/kg/day, 0.03 mg/kg/day, 0.04mg/kg/day, 0.06 mg/kg/day, 0.08 mg/kg/day, 0.12 mg/kg/day, 0.14mg/kg/day, 0.16 mg/kg/day, 0.18 mg/kg/day, 0.2 mg/kg/day, 0.4 mg/kg/day,0.6 mg/kg/day, 0.8 mg/kg/day, 1.0 mg/kg/day, 1.2 mg/kg/day, 1.4mg/kg/day, 1.6 mg/kg/day, 1.8 mg/kg/day, 2.0 mg/kg/day, 2.2 mg/kg/day,2.4 mg/kg/day, or 2.5 mg/kg/day. In some embodiments, the dose of theSV2A inhibitor is 0.1-2.5 mg/kg/day (which, given a typical humansubject of 70 kg, is about 7-180 mg/day), 0.1-0.2 mg/kg/day (which isabout 7-15 mg/day), 0.2-0.4 mg/kg/day (about 14-30 mg/day), 0.4-2.5mg/kg/day (about 25-180 mg/day), 0.6-1.8 mg/kg/day (about 40-130mg/day), 0.04-2.5 mg/kg/day (about 2.5-180 mg/day) or 0.06-1.8 mg/kg/day(about 4-130 mg/day). In some embodiments of the invention, the dose ofthe SV2A inhibitor is 40 to 130 mg, 140 to 300 mg, 200 to 300 mg or 140to 200 mg. Other doses higher than, intermediate to, or less than thesedoses may also be used and may be determined by one skilled in the artfollowing the methods of this invention.

In certain embodiments of the invention, the dose of the SV2A inhibitoris 0.0015 to 7 mg/kg/day (which, given a typical human subject of 70 kg,is about 0.1-500 mg/day). Daily doses that may be used include, but arenot limited to 0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg, 0.005 mg/kg,0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.06 mg/kg,0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg,1.2 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5 mg/kg,4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 6.0 mg/kg, or 7.0 mg/kg; or 0.1 mg,0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg, 3.0mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12mg, 15 mg, 20 mg, 25 mg, 28 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210mg, 225 mg, 250 mg, 280 mg, 300 mg, 350 mg, 400 mg, or 500 mg. In someembodiments, the daily dose of SV2A inhibitor that can be used in themethods of this invention include, without limitation, 0.0015-5 mg/kg(or 0.1-350 mg for a subject of 70 kg), 0.05-4 mg/kg, 0.05-2.0 mg/kg,0.05-1.5 mg/kg, 0.1-1.0 mg/kg, 1-5 mg/kg, 1.5-4.0 mg/kg, 1.8-3.6 mg/kg,0.01-0.8 mg/kg, 0.01-1 mg/kg, 0.01-1.5 mg/kg, 0.01-2 mg/kg, 0.01-2.5mg/kg, 0.01-3 mg/kg, 0.01-3.5 mg/kg, 0.01-4 mg/kg, 0.01-5 mg/kg,0.025-0.8 mg/kg, 0.025-1 mg/kg, 0.025-1.5 mg/kg, 0.025-2 mg/kg,0.025-2.5 mg/kg, 0.025-3 mg/kg, 0.025-3.5 mg/kg, 0.025-4 mg/kg, 0.05-0.8mg/kg, 0.05-1 mg/kg, 0.05-1.5 mg/kg, 0.05-2 mg/kg, 0.05-2.5 mg/kg,0.05-3 mg/kg, 0.05-3.5 mg/kg, 0.05-4 mg/kg, 0.075-0.8 mg/kg, 0.075-1mg/kg, 0.075-1.5 mg/kg, 0.075-2 mg/kg, 0.075-2.5 mg/kg, 0.075-3 mg/kg,0.075-3.5 mg/kg, 0.075-4 mg/kg, 0.1-0.8 mg/kg, 0.1-1 mg/kg, 0.1-1.5mg/kg, 0.1-2 mg/kg, 0.1-2.5 mg/kg, 0.1-3 mg/kg, 0.1-3.5 mg/kg, 0.1-4mg/kg, 0.2-0.8 mg/kg, 0.2-1 mg/kg, 0.2-1.5 mg/kg, 0.2-2 mg/kg, 0.2-2.5mg/kg, 0.2-3 mg/kg, 0.2-3.5 mg/kg, 0.2-4 mg/kg, 0.5-0.8 mg/kg, 0.5-1mg/kg, 0.5-1.5 mg/kg, 0.5-2 mg/kg, 0.5-2.5 mg/kg, 0.5-3 mg/kg, 0.5-3.5mg/kg, or 0.5-4 mg/kg; or 0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg,0.7-180 mg, 0.7-225 mg, 0.7-250 mg, 0.7-280 mg, 1.8-50 mg, 1.8-75 mg,1.8-100 mg, 1.8-150 mg, 1.8-180 mg, 1.8-225 mg, 1.8-250 mg, 1.8-280 mg,3.5-50 mg, 3.5-75 mg, 3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-225 mg,3.5-250 mg, 3.5-280 mg, 5-50 mg, 5-75 mg, 5-100 mg, 5-150 mg, 5-180 mg,5-225 mg, 5-250 mg, 5-280 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg,7-180 mg, 7-225 mg, 7-250 mg, 7-280 mg, 15-50 mg, 15-75 mg, 15-100 mg,15-150 mg, 15-180 mg, 15-225 mg, 15-250 mg, 15-280 mg, 35-50 mg, 35-75mg, 35-100 mg, 35-150 mg, 35-180 mg, 35-225 mg, 35-250 mg, 35-280 mg,0.1-500 mg, 3-300 mg, 3-150 mg, 3-110 mg, 7-70 mg, 70-350 mg, 100-300mg, or 125-250 mg. Other doses higher than, intermediate to, or lessthan these doses may also be used and may be determined by one skilledin the art following the methods of this invention.

In certain embodiments of the invention, the interval of administrationis 12 hours. In certain embodiments of the invention, the interval ofadministration is 24 hours. Administration at less frequent intervals,such as once every 6 hours, may also be used. In some embodiments, theSV2A inhibitor is administered at a total daily dose of 0.1 to 5 mg/kg(e.g., in the case of administration every 12 hours of a daily dose of 2mg/kg, each administration is 1 mg/kg). In some embodiments, the SV2Ainhibitor is administered every 24 hours at a daily dose of 1 to 2mg/kg. In another embodiment, the SV2A inhibitor is administered every24 hours at a daily dose of 0.1-0.2 mg/kg. In some embodiments, the SV2Ainhibitor is administered at a daily dose of 0.01 to 2.5 mg/kg (e.g., inthe case of administration every 12 hours of a daily dose of 0.8 mg/kg,each administration is 0.4 mg/kg). In some embodiments, the SV2Ainhibitor is administered at a daily dose of 0.1 to 2.5 mg/kg. In someembodiments, the SV2A inhibitor is administered at a daily dose of 0.4to 2.5 mg/kg. In some embodiments, the SV2A inhibitor is administered ata daily dose of 0.6 to 1.8 mg/kg. In some embodiments, the selectiveinhibitor of SV2A is administered at a daily dose of 0.04-2.5 mg/kg. Insome embodiments, the selective inhibitor of SV2A is administered at adaily dose of 0.06-1.8 mg/kg. In some embodiments, the selectiveinhibitor of SV2A is administered at a daily dose of 0.001-5 mg/kg. Insome embodiments, the selective inhibitor of SV2A is administered at adaily dose of 0.001-0.5 mg/kg. In some embodiments, the selectiveinhibitor of SV2A is administered at a daily dose of 0.01-0.5 mg/kg.

In certain embodiments of the invention, the SV2A inhibitor islevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. The levetiracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of about 1 to 2 mg/kg, or about 0.1 to 2.5 mg/kg, orabout 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 2.0 to 3.0mg/kg, or about 3.0 to 4.0 mg/kg, or about 2.0 to 4.0 mg/kg, or about0.1 to 5 mg/kg, or about 70 to 140 mg, or about 7 to 180 mg, or about 25to 180 mg, or about 40 to 130 mg, or about 140 to 300 mg, or about 200to 300 mg, or about 140 to 200 mg, or about 7 to 350 mg.

In other embodiments, the levetiracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredaccording to one of the daily dose ranges indicated as “+” listed inTable 1 or Table 2.

TABLE 1 Daily Doses of Levetiracetam Lower range 0.1 0.6 Upper rangemg/kg 0.4 mg/kg mg/kg 1 mg/kg 2 mg/kg 3 mg/kg 1.8 mg/kg   + + + + 2mg/kg + + + + 2.5 mg/kg   + + + + + 3 mg/kg + + + + + 4mg/kg + + + + + + 5 mg/kg + + + + + +

TABLE 2 Daily Doses of Levetiracetam in a Human Subject of 70 KG Lowerrange Upper range 7 mg 25 mg 40 mg 70 mg 140 mg 200 mg 130 mg + + + +140 mg + + + + 180 mg + + + + + 200 mg + + + + + 300 mg + + + + + + 350mg + + + + + +

In certain embodiments of the invention, the SV2A inhibitor islevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. The levetiracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of about 0.1-5 mg/kg, about 1-5 mg/kg, about 1.5-4mg/kg, about 1.8-3.6 mg/kg, about 7-350 mg, about 70-350 mg, about100-300 mg, or about 125-250 mg.

In certain embodiments of the invention, the SV2A inhibitor isbrivaracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. The brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of about 0.1 to 0.2 mg/kg, or about 0.01 to2.5 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, orabout 0.2 to 0.4 mg/kg, or about 7 to 15 mg, or about 0.7 to 180 mg, orabout 2.5 to 180 mg, or about 4.0 to 130 mg, or about 14 to 30 mg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of at least 0.1 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, or2.0 mg, but no more than a daily dose of 2.5 mg, 5 mg, 10 mg, 15 mg, 20mg, 25 mg, 30 mg, or 35 mg. In other embodiments, the brivaracetam orits pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug is administered at a daily dose of at least 0.0015 mg/kg, 0.0075mg/kg, 0.01 mg/kg, 0.015 mg/kg, 0.02 mg/kg, or 0.03 mg/kg, but no morethan a daily dose of 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15mg/kg, 0.1 mg/kg, 0.05 mg/kg, or 0.04 mg/kg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredaccording to one of the daily dose ranges indicated as “+” listed inTable 3 or Table 4. For example, the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be administered at a daily dose of 0.1-35 mg, 0.5-35mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg,0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg,0.0075-0.5 mg/kg, 0.01-0.5 mg/kg, 0.015-0.5 mg/kg, 0.02-0.5 mg/kg,0.03-0.5 mg/kg, 0.0015-0.4 mg/kg, 0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg,0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0.05 mg/kg, or 0.0015-0.04mg/kg.

TABLE 3 Daily Doses of Brivaracetam Lower range 0.0015 0.0075 0.01 0.0150.02 0.03 Upper range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg 0.04mg/kg  + + + + + + 0.05 mg/kg  + + + + + + 0.1 mg/kg + + + + + + 0.15mg/kg  + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4mg/kg + + + + + + 0.5 mg/kg + + + + + +

TABLE 4 Daily Doses of Brivaracetam in a Human Subject of 70 KG Lowerrange Upper range 0.1 mg 0.5 mg 0.75 mg 1.0 mg 1.5 mg 2.0 mg 2.5mg  + + + + + +  5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of at least 0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg,0.005 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg,0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg,0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, but no more than a daily dose of 1mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg,2.2 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5mg/kg, 4.0 mg/kg, 4.5 mg/kg, or 5.0 mg/kg. In other embodiments, thebrivaracetam or its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug is administered at a daily dose of at least 0.1mg, 0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg,3.0 mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 10 mg, 15 mg, 20 mg,25 mg, 28 mg, 30 mg, or 35 mg but no more than a daily dose of 70 mg, 80mg, 85 mg, 100 mg, 110 mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180mg, 190 mg, 200 mg, 210 mg, 225 mg, 250 mg, 280 mg, 300 mg, or 350 mg.In some embodiments, the brivaracetam or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof may beadministered at a daily dose of 0.0015-5 mg/kg, 0.1-350 mg, 0.01-5mg/kg, 0.7-350 mg, 0.05-4 mg/kg, 3-300 mg, 0.05-2.0 mg/kg, 3-150 mg,0.05-1.5 mg, 3-110 mg, 0.1-1.0 mg/kg, 7-70 mg.

In other embodiments, the brivaracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredaccording to one of the daily dose ranges indicated as “+” listed inTable 5 or Table 6. For example, the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be administered at a daily dose of 0.01-0.8 mg/kg,0.01-1 mg/kg, 0.01-1.5 mg/kg, 0.01-2 mg/kg, 0.01-2.5 mg/kg, 0.01-3mg/kg, 0.01-3.5 mg/kg, 0.01-4 mg/kg, 0.01-5 mg/kg, 0.025-0.8 mg/kg,0.025-1 mg/kg, 0.025-1.5 mg/kg, 0.025-2 mg/kg, 0.025-2.5 mg/kg, 0.025-3mg/kg, 0.025-3.5 mg/kg, 0.025-4 mg/kg, 0.05-0.8 mg/kg, 0.05-1 mg/kg,0.05-1.5 mg/kg, 0.05-2 mg/kg, 0.05-2.5 mg/kg, 0.05-3 mg/kg, 0.05-3.5mg/kg, 0.05-4 mg/kg, 0.075-0.8 mg/kg, 0.075-1 mg/kg, 0.075-1.5 mg/kg,0.075-2 mg/kg, 0.075-2.5 mg/kg, 0.075-3 mg/kg, 0.075-3.5 mg/kg, 0.075-4mg/kg, 0.1-0.8 mg/kg, 0.1-1 mg/kg, 0.1-1.5 mg/kg, 0.1-2 mg/kg, 0.1-2.5mg/kg, 0.1-3 mg/kg, 0.1-3.5 mg/kg, 0.1-4 mg/kg, 0.2-0.8 mg/kg, 0.2-1mg/kg, 0.2-1.5 mg/kg, 0.2-2 mg/kg, 0.2-2.5 mg/kg, 0.2-3 mg/kg, 0.2-3.5mg/kg, 0.2-4 mg/kg, 0.5-0.8 mg/kg, 0.5-1 mg/kg, 0.5-1.5 mg/kg, 0.5-2mg/kg, 0.5-2.5 mg/kg, 0.5-3 mg/kg, 0.5-3.5 mg/kg, or 0.5-4 mg/kg; or0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg,0.7-250 mg, 0.7-280 mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg,1.8-180 mg, 1.8-225 mg, 1.8-250 mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg,3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg,5-50 mg, 5-75 mg, 5-100 mg, 5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg,5-280 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg,7-250 mg, 7-280 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg,15-225 mg, 15-250 mg, 15-280 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150mg, 35-180 mg, 35-225 mg, 35-250 mg, or 35-280 mg.

TABLE 5 Daily Doses of Brivaracetam (mg/kg) Lower range Upper range0.0015 0.01 0.025 0.04 0.05 0.075 0.1 0.2 0.5 0.8 + + + + + + + + +1 + + + + + + + + + 1.5 + + + + + + + + + 2 + + + + + + + + +2.5 + + + + + + + + + 3 + + + + + + + + + 3.5 + + + + + + + + +4 + + + + + + + + + 5 + + + + + + + + +

TABLE 6 Daily Doses of Brivaracetam in a Human Subject of 70 KG (mg)Lower range Upper range 0.1 0.7 1.8 3.0 3.5 5 7 15 3550 + + + + + + + + + 75 + + + + + + + + + 100 + + + + + + + + +110 + + + + + + + + + 150 + + + + + + + + + 180 + + + + + + + + +225 + + + + + + + + + 250 + + + + + + + + + 280 + + + + + + + + +300 + + + + + + + + + 350 + + + + + + + + +

In certain embodiments of the invention, the SV2A inhibitor isseletracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof. In some embodiments, the seletracetam orits pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of at least 0.1 mg, 0.5mg, 0.75 mg, 1.0 mg, 1.5 mg, or 2.0 mg, but no more than a daily dose of2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg. In otherembodiments, the seletracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015mg/kg, 0.02 mg/kg, or 0.03 mg/kg, but no more than a daily dose of 0.5mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05mg/kg, or 0.04 mg/kg.

In certain embodiments of the invention, the seletracetam or itspharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug is administered according to one of the daily dose rangesindicated as “+” listed in Table 7 or Table 8. For example, theseletracetam or its pharmaceutically acceptable salt, hydrate, solvateor polymorph may be administered at a daily dose of 0.1-35 mg, 0.5-35mg, 0.75-35 mg, 1.0-35 mg, 1.5-35 mg, 2.0-35 mg, 0.1-30 mg, 0.1-25 mg,0.1-20 mg, 0.1-15 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2.5 mg, 0.0015-0.5 mg/kg,0.0075-0.5 mg/kg, 0.01-0.5 mg/kg, 0.015-0.5 mg/kg, 0.02-0.5 mg/kg,0.03-0.5 mg/kg, 0.0015-0.4 mg/kg, 0.0015-0.3 mg/kg, 0.0015-0.2 mg/kg,0.0015-0.15 mg/kg, 0.0015-0.1 mg/kg, 0.0015-0.05 mg/kg, or 0.0015-0.04mg/kg.

TABLE 7 Daily Doses of Seletracetam Lower range 0.0015 0.0075 0.01 0.0150.02 0.03 Upper range mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg 0.04mg/kg  + + + + + + 0.05 mg/kg  + + + + + + 0.1 mg/kg + + + + + + 0.15mg/kg  + + + + + + 0.2 mg/kg + + + + + + 0.3 mg/kg + + + + + + 0.4mg/kg + + + + + + 0.5 mg/kg + + + + + +

TABLE 8 Daily Doses of Seletracetam in a Human Subject of 70 KG Lowerrange Upper range 0.1 mg 0.5 mg 0.75 mg 1.0 mg 1.5 mg 2.0 mg 2.5mg  + + + + + +  5 mg + + + + + + 10 mg + + + + + + 15 mg + + + + + + 20mg + + + + + + 25 mg + + + + + + 30 mg + + + + + + 35 mg + + + + + +

In other embodiments, the seletracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredat a daily dose of at least 0.0015 mg/kg, 0.002 mg/kg, 0.0025 mg/kg,0.005 mg/kg, 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg,0.06 mg/kg, 0.07 mg/kg, 0.08 mg/kg, 0.09 mg/kg, 0.1 mg/kg, 0.2 mg/kg,0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, but no more than a daily dose of 1mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg,2.2 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.5mg/kg, 4.0 mg/kg, 4.5 mg/kg, or 5.0 mg/kg. In other embodiments, theseletracetam or its pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug is administered at a daily dose of at least 0.1mg, 0.15 mg, 0.18 mg, 0.35 mg, 0.7 mg, 1.5 mg, 2.0 mg, 2.5 mg, 2.8 mg,3.0 mg, 3.5 mg, 4.2 mg, 5 mg, 5.5 mg, 6.0 mg, 7 mg, 10 mg, 15 mg, 20 mg,25 mg, 28 mg, 30 mg, or 35 mg but no more than a daily dose of 70 mg, 80mg, 85 mg, 100 mg, 110 mg, 125 mg, 140 mg, 150 mg, 170 mg, 175 mg, 180mg, 190 mg, 200 mg, 210 mg, 225 mg, 250 mg, 280 mg, 300 mg, or 350 mg.In some embodiments, the brivaracetam or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof may beadministered at a daily dose of 0.0015-5 mg/kg, 0.1-350 mg, 0.01-5mg/kg, 0.7-350 mg, 0.05-4 mg/kg, 3-300 mg, 0.05-2.0 mg/kg, 3-150 mg,0.05-1.5 mg, 3-110 mg, 0.1-1.0 mg/kg, 7-70 mg.

In other embodiments, the seletracetam or its pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug is administeredaccording to one of the daily dose ranges indicated as “+” listed inTable 9 or Table 10. For example, the seletracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof may be administered at a daily dose of 0.01-0.8 mg/kg,0.01-1 mg/kg, 0.01-1.5 mg/kg, 0.01-2 mg/kg, 0.01-2.5 mg/kg, 0.01-3mg/kg, 0.01-3.5 mg/kg, 0.01-4 mg/kg, 0.01-5 mg/kg, 0.025-0.8 mg/kg,0.025-1 mg/kg, 0.025-1.5 mg/kg, 0.025-2 mg/kg, 0.025-2.5 mg/kg, 0.025-3mg/kg, 0.025-3.5 mg/kg, 0.025-4 mg/kg, 0.05-0.8 mg/kg, 0.05-1 mg/kg,0.05-1.5 mg/kg, 0.05-2 mg/kg, 0.05-2.5 mg/kg, 0.05-3 mg/kg, 0.05-3.5mg/kg, 0.05-4 mg/kg, 0.075-0.8 mg/kg, 0.075-1 mg/kg, 0.075-1.5 mg/kg,0.075-2 mg/kg, 0.075-2.5 mg/kg, 0.075-3 mg/kg, 0.075-3.5 mg/kg, 0.075-4mg/kg, 0.1-0.8 mg/kg, 0.1-1 mg/kg, 0.1-1.5 mg/kg, 0.1-2 mg/kg, 0.1-2.5mg/kg, 0.1-3 mg/kg, 0.1-3.5 mg/kg, 0.1-4 mg/kg, 0.2-0.8 mg/kg, 0.2-1mg/kg, 0.2-1.5 mg/kg, 0.2-2 mg/kg, 0.2-2.5 mg/kg, 0.2-3 mg/kg, 0.2-3.5mg/kg, 0.2-4 mg/kg, 0.5-0.8 mg/kg, 0.5-1 mg/kg, 0.5-1.5 mg/kg, 0.5-2mg/kg, 0.5-2.5 mg/kg, 0.5-3 mg/kg, 0.5-3.5 mg/kg, or 0.5-4 mg/kg; or0.7-50 mg, 0.7-75 mg, 0.7-100 mg, 0.7-150 mg, 0.7-180 mg, 0.7-225 mg,0.7-250 mg, 0.7-280 mg, 1.8-50 mg, 1.8-75 mg, 1.8-100 mg, 1.8-150 mg,1.8-180 mg, 1.8-225 mg, 1.8-250 mg, 1.8-280 mg, 3.5-50 mg, 3.5-75 mg,3.5-100 mg, 3.5-150 mg, 3.5-180 mg, 3.5-225 mg, 3.5-250 mg, 3.5-280 mg,5-50 mg, 5-75 mg, 5-100 mg, 5-150 mg, 5-180 mg, 5-225 mg, 5-250 mg,5-280 mg, 7-50 mg, 7-75 mg, 7-100 mg, 7-150 mg, 7-180 mg, 7-225 mg,7-250 mg, 7-280 mg, 15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-180 mg,15-225 mg, 15-250 mg, 15-280 mg, 35-50 mg, 35-75 mg, 35-100 mg, 35-150mg, 35-180 mg, 35-225 mg, 35-250 mg, or 35-280 mg.

TABLE 9 Daily Doses of Seletracetam (mg/kg) Lower range Upper range0.0015 0.01 0.025 0.04 0.05 0.075 0.1 0.2 0.5 0.8 + + + + + + + + +1 + + + + + + + + + 1.5 + + + + + + + + + 2 + + + + + + + + +2.5 + + + + + + + + + 3 + + + + + + + + + 3.5 + + + + + + + + +4 + + + + + + + + + 5 + + + + + + + + +

TABLE 10 Daily Doses of Seletracetam in a Human Subject of 70 KG (mg)Lower range Upper range 0.1 0.7 1.8 3.0 3.5 5 7 15 3550 + + + + + + + + + 75 + + + + + + + + + 100 + + + + + + + + +110 + + + + + + + + + 150 + + + + + + + + + 180 + + + + + + + + +225 + + + + + + + + + 250 + + + + + + + + + 280 + + + + + + + + +300 + + + + + + + + + 350 + + + + + + + + +

The SV2A inhibitor or its pharmaceutically acceptable salt, hydrate,solvate or polymorph may be administered at a subtherapeutic dosagelevel when provided in combination with valproate or its analog,derivative or pharmaceutically acceptable salt, due tovalproate-dependent increase in the therapeutic index of the SV2Ainhibitor. In some embodiments, the increase in the therapeutic index ofthe SV2A inhibitor, due to the combination with valproate, is greaterthan the therapeutic index of the SV2A inhibitor administered in theabsence of the valproate by at least about 1.5× or 2.0× or 2.5× or 3.0×or 3.5× or 4.0× or 4.5× or 5.0× or 5.5× or 6.0× or 6.5× or 7.0× or 7.5×or 8.0× or 8.5× or 9.0× or 9.5× or 10×, or greater than about 10×. Insome embodiments, combinations of an SV2A inhibitor with valproatereduces the dosage of the SV2A inhibitor required for its therapeuticeffect. In some embodiments of the invention, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof that is administered in combination with valproate orits analog, derivative or pharmaceutically acceptable salt isadministered at a daily dose of about 0.001 mg/kg to 5 mg/kg, or about0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2 mg/kg, orabout 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, or about0.06 to 1.8 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg,or about 0.5 mg/kg to 5 mg/kg, or about 0.05 mg/kg to 0.5 mg/kg. In someembodiments, the amount of the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof that isadministered in combination with valproate or its analog, derivative orpharmaceutically acceptable salt is a subtherapeutic amount (as comparedto the therapeutic dose of valproate when administered alone). Suchsubtherapeutic amount, may be, for example, a daily dose, administeredat a daily dose of less than 5 mg/kg, less than 2.5 mg/kg, less than 2mg/kg, less than 1.75 mg/kg, less than 1.6 mg/kg, less than 1.5 mg/kg,less than 1 mg/kg, less than 0.8 mg/kg, less than 0.6 mg/kg, less than0.5 mg/kg, less than 0.4 mg/kg, less than 0.3 mg/kg, less than 0.2mg/kg, less than 0.1 mg/kg, less than 0.05 mg/kg, less than 0.04 mg/kg,less than 0.03 mg/kg, less than 0.02 mg/kg, less than 0.01 mg/kg, lessthan 0.005 mg/kg, or less than 0.001 mg/kg.

Valproate or its analog, derivative or pharmaceutically acceptable saltmay be administered at a dosage level up to conventional dosage levels.Valproate has been prescribed for treatment of epilepsy, bipolardisorder, migraine, and post-traumatic stress disorder. Valproate isalso reported to be effective in treating cognitive impairment (Koh etal., 36th annual meeting of the Society for Neuroscience, Oct. 15, 2006,No. 273.14, D.3). Chronic subcutaneous administration to memory-impairedaged rats of 100 mg/kg/day sodium valproate treated their cognitiveimpairment and their performance in a memory test was significantlyimproved. This dosage results in a blood total valproate level of 10μg/ml plasma (10 μg/ml total valproate). Treatment with chronicsubcutaneous administration of 50 mg/kg/day valproate, however, was noteffective.

The valproate or its analog, derivative, pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug may be administered atdosage levels distinct from conventional levels when provided incombination with an SV2A inhibitor, due to an SV2A inhibitor-dependentincrease in the valproate's therapeutic index. In some embodiments, theincrease in the valproate's therapeutic index due to the combinationwith an SV2A inhibitor thereof is greater than the therapeutic index ofthe valproate administered in the absence of an SV2A inhibitor by atleast about 1.5× or 2.0× or 2.5× or 3.0× or 3.5× or 4.0× or 4.5× or 5.0×or 5.5× or 6.0× or 6.5× or 7.0× or 7.5× or 8.0× or 8.5× or 9.0× or 9.5×or 10×, or greater than about 10×. In some embodiments, combinations ofvalproate with the SV2A inhibitor reduces the dosage of the valproaterequired for its therapeutic effect. In some embodiments, the amount ofthe valproate or its analog, derivative, pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug administered in combinationwith the SV2A inhibitor is a subtherapeutic amount. In certainembodiments, the dose of valproate or its analog, derivative orpharmaceutically acceptable salt when administered in combination withan SV2A inhibitor is a dose that results in a total blood valproate of0.5 to 5 μg/ml plasma. The doses useful for valproate or its analog,derivative or pharmaceutically acceptable salt are readily determined bythose skilled in the art, using the methods of this invention.

In certain embodiments, wherein an SV2A inhibitor or itspharmaceutically acceptable salt, hydrate, solvate and polymorph isadministered in combination with valproate or its analog, derivative orpharmaceutically acceptable salt, the dosage of both the SV2A inhibitoror its pharmaceutically acceptable salt, hydrate, solvate and polymorphand the valproate or its analog, derivative, pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug, are each sub-therapeuticwith respect to treating a CNS disorder with cognitive impairment whenadministered alone.

In some embodiments, a suitable amount of the SV2A inhibitor isadministered so as to reduce the dose of the valproate (e.g., a doserequired to effect a degree of cognitive function improvement or treatage-associated cognitive impairment) by at least about 20%, at leastabout 30%, at least about 40%, or at least about 50%, at least about60%, at least about 70%, at least about 80%, at least about 90% or morefrom to the dose of valproate normally used when administered alone(i.e., individually and not in combination with other therapeutic agentsor compounds). The reduction may be reflected in terms of amountadministered at a given administration and/or amount administered over agiven period of time (reduced frequency).

In certain embodiments of the invention, the combined administration ofan SV2A inhibitor or its pharmaceutically acceptable salt, hydrate,solvate and polymorph, and valproate or its analog, derivative orpharmaceutically acceptable salt, can attain a longer or improvedtherapeutic effect in the subject than that attained by administeringonly the valproate or only the SV2A inhibitor, by at least about 1.5×,or 2.0×, or 2.5×, or 3.0×, or 3.5×, or 4.0×, or 4.5×, or 5.0×, or 5.5×,or 6.0×, or 6.5×, or 7.0×, or 7.5×, or 8.0×, or 8.5×, or 9.0×, or 9.5×,or 10×, or greater than about 10×.

In certain embodiments of the invention, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form, a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form. In some embodiments, the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form) is formulatedtogether with valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof in asingle formulation. In some embodiments, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form) is formulated together withvalproate or an analog, derivative, pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof are formulated inseparate formulations, which may be packaged together. In some of theabove composition embodiments where the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form), valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is also in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In some of theabove composition embodiments where the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form), valproate or an analog,derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is not in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments of the composition of the present invention, valproate or ananalog, derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments, valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof in anextended release form (or a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form) is formulated together with the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in a single formulation. In some embodiments, valproateor an analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form) and the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof are formulated in separate formulations,which may be packaged together. In some of the above compositionembodiments where valproate or an analog, derivative, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is inan extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form), the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof is alsoin an extended release form (or a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form). In some of the above embodiments where valproate oran analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is in an extended release form(or a controlled release form, a prolonged release form, a sustainedrelease form, a delayed release form, or a slow release form), the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is not in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments, the composition is in a unit dosage form. In otherembodiments, the two components of the compositions are in separatedelivery forms packaged together.

Compositions of the Invention

In one aspect, the invention provides compositions comprising an SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate orpolymorph alone or in combination with valproate or its analog,derivative or pharmaceutically acceptable salt. In some embodiments, theSV2A inhibitor and the valproate may be present in a single dosage unit(e.g., combined together in one capsule, tablet, powder, or liquid,etc.). The composition described herein can contain more than one SV2Ainhibitor its pharmaceutically acceptable salt, hydrate, solvate orpolymorph and/or more than one valproate or its analog, derivative orpharmaceutically acceptable salt. In some embodiments, the SV2Ainhibitor and the valproate are in separate formulations packagedtogether.

The compositions described herein can further contain pharmaceuticallyacceptable excipient(s) and may contain other agents that serve toenhance and/or complement the effectiveness of the SV2A inhibitor and/orthe valproate. The compositions may also contain additional agents knownto be useful for treating cognitive function disorder.

The composition in the present invention may be in solid dosage formssuch as capsules, tablets, dragrees, pills, lozenges, powders andgranule. Where appropriate, they may be prepared with coatings such asenteric coatings or they may be formulated so as to provide controlledreleases of one or more active ingredient such as sustained or prolongedrelease according to methods well known in the art. In certainembodiments, the composition is in form of a slow, controlled, orextended release. The term “extended release” is widely recognized inthe art of pharmaceutical sciences and is used herein to refer to acontrolled release of an active compound or agent from a dosage form toan environment over (throughout or during) an extended period of time,e.g. greater than or equal to one hour. An extended release dosage formwill release drug at substantially constant rate over an extended periodof time or a substantially constant amount of drug will be releasedincrementally over an extended period of time. The term “extendedrelease” used herein includes the terms “controlled release”, “prolongedrelease”, “sustained release”, or “slow release”, as these terms areused in the pharmaceutical sciences. In some embodiments, the extendedrelease dosage is administered in the form of a patch or a pump. Thecomposition may also be in liquid dosage forms including solutions,emulsions, suspensions, syrups, and elixirs. The term “extended release”used herein includes the terms “controlled release,” “prolongedrelease,” “sustained release,” “delayed release,” or “slow release” asthese terms are used in the pharmaceutical sciences. In someembodiments, the extended release dosage is administered in the form ofa patch or a pump. The term “Extended release dosage form” or “extendedrelease form”, as used herein, also refers to a dosage form thatcontains one or more active ingredients, where the release of at leastone of the active ingredient, when placed in water or other biologicalfluids or solvents, may occur over an extended period, such as a periodof at least about 1 day, at least about 2 days, at least about 3 days,at least about 4 days, at least about 5 days, at least about 10 days, atleast about 20 days, at least about 30 days, at least about 60 days, atleast about 90 days, or at least about 150 days. In some embodiments ofthe present invention, only one of the SV2A inhibitor and valproate isin an extended release dosage form. In some other embodiments of thecomposition of the present invention, the SV2A inhibitor and valproateare each in an extended release dosage form (together in one formulationor separately in two formulations).

In certain embodiments of the invention, the pharmaceutical compositioncomprising an SV2A inhibitor (e.g., levetiracetam, brivaracetam, orseletracetam) or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an extended release form, acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form.

In certain embodiments of the invention, the pharmaceutical compositioncomprising an SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof and valproate or ananalog, derivative, pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments, the pharmaceutical composition comprising an SV2A inhibitoror a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form) and further comprising valproateor an analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug in an extended release form (or acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form). In someembodiments, the pharmaceutical composition comprising an SV2A inhibitoror a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in an extended release form (or a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form) and further comprising valproateor an analog, derivative, pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug that is not an extended release form, ora controlled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form. In someembodiments, the pharmaceutical composition comprising an SV2A inhibitoror a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof that is not in an extended release form (or a controlledrelease form, a prolonged release form, a sustained release form, adelayed release form, or a slow release form) and further comprisingvalproate or an analog, derivative, pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug that is in an extended releaseform, or a controlled release form, a prolonged release form, asustained release form, a delayed release form, or a slow release form.

The compositions may be specifically formulated for administration byany suitable route as described herein and known in the art.Compositions for parental administration include sterile aqueous andnonaqueous injectable solutions, dispersions, suspensions or emulsionsas well as sterile powders to be reconstituted in sterile injectablesolutions or dispersions prior to use. Compositions for intraoral andoral delivery (including sublingual and buccal administration, e.g.Danckwerts et al, and oral) include but are not limited to bioadhesivepolymers, tablets, patches, liquids and semisolids (see e.g., Smart etal). Compositions for respiratory delivery (pulmonary and nasaldelivery) include but are not limited to a variety of pressurizedmetered dose inhalers, dry powder inhalers, nebulizers, aqueous mistinhalers, drops, solutions, suspensions, sprays, powders, gels,ointments, and specialized systems such as liposomes and microspheres(see e.g. Owens et al, “Alternative Routes of Insulin Delivery” andMartini et al). Compositions for transdermal delivery include but arenot limited to colloids, patches, and microemulsions. Other suitableadministration forms for the above and other include depot injectableformulations, suppositories, sprays, ointments, cremes, gels, inhalants,dermal patches, implants etc.

The compositions may also contain adjuvants, such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption, such as aluminum monostearate andgelatin.

Therapeutic formulations can be prepared by methods well known in theart of pharmacy, see, e.g., Goodman et al., 2001; Ansel, et al., 2004;Stoklosa et al., 2001; and Bustamante, et al., 1993.

In certain embodiments of the invention, a composition containing anSV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvateor polymorph comprises the SV2A inhibitor in an amount of 0.07-60 mg,0.07-350 mg, 25-60 mg, 25-125 mg, 50-250 mg, 5-140 mg, 0.7-180 mg,125-240 mg, 3-50 mg, or 3-60 mg. In some embodiments, a compositioncontaining an SV2A inhibitor or its pharmaceutically acceptable salt,hydrate, solvate or polymorph comprises the SV2A inhibitor in an amountof 0.05-35 mg.

In certain embodiments of the invention, a composition containing anSV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvateor polymorph, in combination with valproate or its analog, derivative orpharmaceutically acceptable salt comprises an amount of the SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvate orpolymorph of 0.05-35 mg, 0.07-60 mg, 0.07-350 mg, 25-60 mg, 25-125 mg,50-250 mg, 5-15 mg, 5-30 mg, 5-140 mg, 0.7-180 mg, 125-240 mg, 3-50 mg,or 0.07-50 mg, or 3-60 mg. In some embodiments, the amount of the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is less than 350 mg, less than 250 mg,less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg,less than 35 mg, less than 10 mg, less than 5 mg, less than 1 mg, lessthan 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg.

In certain embodiments of the invention, a composition containing anSV2A inhibitor or its pharmaceutically acceptable salt, hydrate, solvateor polymorph, in combination with valproate or its analog, derivative orpharmaceutically acceptable salt comprises an amount of the SV2Ainhibitor or its pharmaceutically acceptable salt, hydrate, solvate orpolymorph of 0.1-500 mg, 0.1-300 mg, 0.7-300 mg, 3-300 mg, 3-150 mg,3-110 mg, 7-70 mg, 7-300 mg, 70-300 mg, 100-300 mg, 125-250 mg, 0.5-50mg, 0.5-75 mg, 0.5-100 mg, 0.5-150 mg, 0.5-200 mg, 0.5-225 mg, 0.5-250mg, 0.5-300 mg, 1.5-50 mg, 1.5-75 mg, 1.5-100 mg, 1.5-150 mg, 1.5-200mg, 1.5-225 mg, 1.5-250 mg, 1.5-300 mg, 3-50 mg, 3-75 mg, 3-100 mg,3-150 mg, 3-200 mg, 3-225 mg, 3-250 mg, 3-300 mg, 5-50 mg, 5-75 mg,5-100 mg, 5-150 mg, 5-200 mg, 5-225 mg, 5-250 mg, 5-300 mg, 7-50 mg,7-75 mg, 7-100 mg, 7-150 mg, 7-200 mg, 7-225 mg, 7-250 mg, 7-300 mg,15-50 mg, 15-75 mg, 15-100 mg, 15-150 mg, 15-200 mg, 15-225 mg, 15-250mg, 15-300 mg, 30-50 mg, 30-75 mg, 30-100 mg, 30-150 mg, 30-200 mg,30-225 mg, 30-250 mg, or 30-300 mg.

In addition to an SV2A inhibitor or its pharmaceutically acceptablesalt, hydrate, solvate and polymorph, alone or in combination withvalproate or its analog, derivative or pharmaceutically acceptable salt,the compositions and methods of this invention can also include othertherapeutically useful agents. These other therapeutically useful agentsmay be administered in a single formulation, simultaneously orsequentially according to the methods of the invention.

It will be understood by one of ordinary skill in the art that thecompositions and methods described herein may be adapted and modified asis appropriate for the application being addressed and that thecompositions and methods described herein may be employed in othersuitable applications, and that such other additions and modificationswill not depart from the scope hereof.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the embodiments which followthereafter.

EXAMPLES Introduction and Models of Cognitive Impairment

A variety of conditions characterized by cognitive impairment, e.g.,Age-Associated Memory Impairment (AAMI), Mild Cognitive Impairment (MCI)and Age-related Cognitive Decline (ARCD) are believed to be related toaging. Others are related to disease, for example, AD. Animal modelsserve as an important resource for developing and evaluating treatmentsfor such age-related cognitive impairments. Features that characterizeage-related cognitive impairment in animal models typically extend toage-related cognitive impairment in humans. Efficacy in such animalmodels is, thus, predictive of efficacy in humans.

Of available models, a Long-Evans rat model of cognitive impairment isparticularly well suited for distinguishing the difference betweencognitive impairment related to illness and that related to aging.Indeed, extensive behavioral characterization has identified a naturallyoccurring form of cognitive impairment in an outbred strain of agedLong-Evans rats (Charles River Laboratories; Gallagher et al., Behav.Neurosci. 107:618-626, (1993)). In a behavioral assessment with theMorris Water Maze (MWM), rats learn and remember the location of anescape platform guided by a configuration of spatial cues surroundingthe maze. The cognitive basis of performance is tested in probe trialsusing measures of the animal's spatial bias in searching for thelocation of the escape platform. Aged rats in the study population haveno difficulty swimming to a visible platform, but an age-dependentimpairment is detected when the platform is camouflaged, requiring theuse of spatial information. Performance for individual aged rats in theoutbred Long-Evans strain varies greatly. For example, a proportion ofthose rats perform on a par with young adults. However, approximately40-50% fall outside the range of young performance. This variabilityamong aged rats reflects reliable individual differences. Thus, withinthe aged population some animals are cognitively impaired and designatedaged-impaired (AI) and other animals are not impaired and are designatedaged-unimpaired (AU). See, e.g., Colombo et al., Proc. Natl. Acad. Sci.94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10:691-708, (1989); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); andNicolle et al., J. Neurosci. 19: 9604-9610, (1999).

We used the above-described rat model to identify individual AI and AUrats. We then conducted behavioral assessment on AI rats whileadministering various pharmacological treatments.

Example 1 Increased Gene Expression of SV2A in Aged-Impaired RatsBehavioral Characterization of Young, Aged-Impaired and Aged-UnimpairedRats in Morris Water Maze (MWM)

Behavioral tests were performed on young (4 months old) and aged (24months old) pathogen-free male Long-Evans rats.

The MWM apparatus consists of a large, circular pool (diameter 1.53 m;height, 0.58 m) filled with water (27° C.) that is made opaque throughthe addition of non-toxic pigment or some other substance. In thetypical “hidden platform” version of the test, rats are trained to finda camouflaged white escape platform (height, 34.5 cm) that is positionedin the center of one quadrant of the maze about 1.0 cm below the watersurface. This platform can be retracted to the bottom of the tank orraised to its normal position from outside the maze during behavioraltesting. The location of the platform remains constant from trial totrial. Because there are no local cues that mark the position of theplatform, the rat's ability to locate it efficiently from any startingposition at the perimeter of the pool depends on using informationsurrounding the maze. The maze is surrounded by black curtains to whichwhite patterns are affixed to provide a configuration of spatial cues. Asecond platform (height 37.5 cm), with its surface painted black iselevated 2 cm above the water surface during cue training to control forfactors unrelated to cognition. The behavior of a rat in the pool isrecorded by a camera that is suspended 2.5 m above the center of thepool. The camera is connected to a video tracking system (HVS ImageAdvanced Tracker VP200) and a PC computer running HVS software developedby Richard Baker of HVS Image, Hampton, UK.

The MWM protocol is optimized for sensitivity to the effects of aging oncognition and for measures of reliable individual differences within theaged population of out-bred Long-Evans rats (Gallagher et al. Behav.Neurosci. 107:618-626, (1993)). Rats receive three trials per day for 8consecutive days, using a 60 sec inter-trial interval. On each trainingtrial, the rat is released into the maze from one of four equally spacedstarting positions around the perimeter of the pool. The startingposition varies from trial to trial, thus preventing the use of aresponse strategy (e.g., always turning left from the start location tolocate the escape platform). If a rat does not locate the escapeplatform within 90 sec on any trial, the experimenter guides the rat tothe platform, where it remains for 30 sec. Every sixth trial consists ofa probe trial to assess the development of spatial bias in the maze.During these trials, the rat swims with the platform retracted to thebottom of the pool for 30 sec, at which time the platform is raised toits normal position for completion of the escape trial. At thecompletion of the protocol using the hidden platform, rats are assessedfor cue learning using the visible platform. The location of thisplatform varies from trial to trial in a single session of 6 trainingtrials.

The proximity of the animal's position with respect to the goal is usedto analyze the training trial and probe trial performance. The proximitymeasure is obtained by sampling the position of the animal in the maze(10 times/sec) to provide a record of distance from the escape platformin 1 sec averages. For both probe trials and training trials, acorrection procedure is implemented so that trial performance isrelatively unbiased by differences in distance to the goal from thevarious start locations at the perimeter of the pool. In making thiscorrection, the average swimming speed is calculated for each trial(path length/latency). Then, the amount of time required to swim to thegoal at that speed from the start location used for the trial is removedfrom the record prior to computing trial performance, i.e., cumulativedistance on training trials and average distance from the goal on probetrials. Thus, scores obtained using the proximity measure are designedto reflect search error, representing deviations from an optimal search,i.e. direct path to the goal and search in the immediate vicinity ofthat location during probe trials.

Computer records of video-tracking are compiled to provide data on eachrat's performance in the maze. Measures on training trials and probetrials are analyzed by Analysis of Variance (ANOVA).

In one set of trials, the performance during training with the hidden,camouflaged platform differs between the groups of young and aged rats[F (1, 23)=12.69, p<0.002]. In this set of trials, no difference betweenthe groups is observed for the cue training trials with a visibleplatform. In this set of trials, latencies to escape during cue trainingaveraged 9.36 seconds for young and 10.60 seconds for the aged rats.

An average proximity measure on interpolated probe trials is used tocalculate a spatial learning index for each individual subject asdescribed in detail in Gallagher et al., Behav. Neurosci. 107:618-26,(1993). When a rat rapidly learns to search for the platform close toits position, its spatial learning index is low. Overall, in one set oftrials aged rats differed from young rats [F (1, 23)=15.18, p<0.001].Aged rats are classified as either unimpaired or impaired relative tothe learning index profile of the young study population. Aged rats thatfall within the normative range of young rats (index scores <241) aredesignated aged-unimpaired (AU). The remaining aged subjects that haveindex scores outside the range of young performance are designatedaged-impaired (AI).

Preparation of RNA from Behaviorally Characterized Rats

Twenty-four outbred Long-Evans rats, behaviorally characterized as isdescribed above, are killed by live decapitation to obtain fresh braintissue. The brain is removed, and the dentate gyms hippocampal region ismicrodissected from 500 micron sections taken through the transverseaxis of the entire hippocampal formation (both left and righthippocampi) of 24 characterized rats. There are 8 animals in each group(AI, AU, and Y).

Total RNA is isolated using Trizol reagent (Invitrogen, Carlsbad,Calif.) according to the standard protocol (homogenization in Trizolreagent followed by chloroform extraction and isopropanolprecipitation). Total RNA is further purified using the RNeasy mini kit(Qiagen, Valencia, Calif.). cRNA probes are then generated from the RNAsamples at the Johns Hopkins Microarray Core Facility, generallyaccording to Affymetrix specifications.

Briefly, 5 μg of total RNA is used to synthesize first strand cDNA usingoligonucleotide probes with 24 oligo-dT plus T7 promoter as primer(Proligo LLC, Boulder, Calif.), and the SuperScript Choice System(Invitrogen). Following the double stranded cDNA synthesis, the productis purified by phenol-chloroform extraction, and biotinilated anti-sensecRNA is generated through in vitro transcription using the BioArray RNAHigh Yield Transcript Labeling kit (ENZO Life Sciences Inc.,Farmingdale, N.Y.). 15 μg of the biotinilated cRNA is fragmented at 94°C. for 35 min (100 mM Trix-acetate, pH 8.2, 500 mM KOAC, 150 mM MgOAC).10 μg of total fragmented cRNA is hybridized to the RAT genome 230-2Affymetrix GeneChip array for 16 hours at 45° C. with constant rotation(60 rpm).

Affymetrix Fluidics Station 450 is then used to wash and stain thechips, removing the non-hybridized target and incubating with astreptavidin-phycoerythrin conjugate to stain the biotinilated cRNA. Thestaining is then amplified using goat immunoglobulin-G (IgG) as blockingreagent and biotinilated anti-streptavidin antibody (goat), followed bya second staining step with a streptavidin-phycoerythrin conjugate.

For quality control of the total RNA from the samples, the AgilentBioanalyzer, Lab on a Chip technology, is used to confirm that all thesamples had optimal rRNA ratios (1:2, for 18S and 28S, respectively) andclean run patterns.

For quality control of the hybridization, chip image, and comparisonbetween chips, the following parameters are considered: Scaling factor:related to the overall intensity of the chip, to confirm the similarsignal intensity and staining through out the samples; Background:estimation of unspecific or cross-hybridization; Percentage of presentcalls: percentage of transcripts that are considered significantlyhybridized to the chip (present) by the algorithm;Glyseraldehyde-3-phosphate dehydrogenase (GAPDH) (3′/5′): representationof the RNA integrity by measuring the ratio of 3′ to 5′ regions for thehousekeeping gene GAPDH, its presence in the chip and a ratio close to 1advocates for a good integrity of the target (sample); Spikes(BioB/BioC) to confirm the detection level and sensitivity afterhybridization.

Data Analysis of Microarray

Fluorescence is detected using the Affymetrix G3000 GeneArray Scannerand image analysis of each GeneChip is done through the GeneChipOperating System 1.1.1 (GCOS) software from Affymetrix, using thestandard default settings. All of the GeneChip arrays use shortoligonucleotides for genes in an RNA sample.

For comparison between different chips, global scaling is used, scalingall probe sets to target intensity (TGT) of 150. Total number of presentcalls and scaling factors are similar across all chips. Further analysisfor presence/absence and statistical difference is performed on a regionby region basis in the following manner. Probe sets are determined to bepresent in a region if it had a present call in four of eight animals ina single group.

Probe sets are annotated using the Affymetrix annotation of Jun. 20,2005, and all probe sets representing a specific gene are identified.

An ANOVA is conducted on the probe set signal values for all presentprobe sets by combining two groups of animals and comparing them to thethird group. An “AI ANOVA” is performed, where AU group are combinedwith Young group and compared to AI group.

Pearsons's correlations comparing probe set signal values to learningindices were calculated for the aged animals (excluding young) acrossall present probe sets. As shown in FIG. 1, expression of genes encodingSV2A was significantly increased in aged-impaired (AI) individualsrelative to young individuals (Y) and aged-unimpaired individuals (AU)in a set of experiments performed as above. These results show thatincreased SV2A expression was correlated to the development ofage-related cognitive impairment.

Example 2 Effect of Levetiracetam in Aged-Impaired Rats Morris WaterMaze Results

Six Age-Impaired (AI) Long-Evans rats (as characterized above) weretested for their memory of new spatial information in the MWM, underdifferent drug/control treatment conditions (vehicle control and twodifferent dosage levels of levetiracetam). The MWM protocol wassubstantially the same as the one described in Example 1. Specificallyfor this study, a retention trial was performed after the trainingtrials, as described below.

AI rats were given six training trials per training day with a 60-secinter-trial interval between each training trial for two consecutivedays. On each training trial, the rat was released in the maze from oneof four equally spaced starting positions around the perimeter of thepool. If the rat did not locate the escape platform within 90 sec on anytrial, the experimenter guided the rat to the platform, where itremained for 30 sec. 30 minutes to 1 hour prior to all the trainingtrials on each training day, AI rats were pretreated with one of threedrug conditions: 1) vehicle control (0.9% saline solution); 2)levetiracetam (5 m/kg/day); and 3) levetiracetam (10 mg/kg/day); throughintraperitoneal (i.p.) injection. The same six AI rats were used for theentire trials so that each treatment condition was tested on all sixrats. Therefore, to counterbalance any potential bias, both the locationof the escape platform and the spatial cues surrounding the water mazewere different in the three treatment conditions. Therefore, using oneset of locations and spatial cues, two rats were treated with salinecontrol solution, two with levetiracetam (5 m/kg/day) and two withlevetiracetam (10 mg/kg/day). Using the second set of locations andspatial cues, the two rats treated with saline control solution in thefirst test were treated with either levetiracetam (5 m/kg/day) orlevetiracetam (10 mg/kg/day), and the two rats previously treated withlevetiracetam (5 m/kg/day) were treated with either saline controlsolution or levetiracetam (10 mg/kg/day), and the two rats previouslytreated with levetiracetam (10 mg/kg/day) were treated with eithersaline control solution or levetiracetam (5 m/kg/day). Using the lastset of locations and spatial cues, the rat groupings were again switchedso that each group was treated with a different condition than they hadbeen treated previously.

After the second training day and completion of the twelve trainingtrials (over the two days), the rat was returned to its home cage andplaced in the animal housing room. After a delay of 24 hours from thelast training trial, the rat was given one testing trial (the “retentiontrial”), which was the same MWM task as the training trials, but withthe escape platform removed.

For the retention trial, the MWM circular pool was divided into 4quadrants. The particular quadrant where the escape platform was placedin the training trials is referred as “target quadrant”. The particularregion where the platform was located in the training trials is referredas “target annulus”. In the retention trial, the time the AI rats spentswimming in the target quadrant is measured and further plotted as apercentage of total swimming time. FIG. 2 displays the results of onesuch set of retention trials. The time the AI rats spend in the targetannulus is also measured. FIG. 2 displays the results of one such set ofretention trials. Time data are collected for all three drug treatmentconditions.

In the retention trial, whose results are depicted in FIG. 2, the timethe AI rats spent in the target quadrant was approximately 25%, which isa performance equivalent to them having no memory of the platformlocation. This performance did not significantly improve in the grouptreated with levetiractam at 5 mg/kg/day. However, the group treatedwith levetiractam at 10 mg/kg/day demonstrated significantly improvedmemory as compared to vehicle-treated controls, as indicated by asignificant increase in the time spent in the target quadrant toapproximately 35% of total swimming time (see FIG. 2). That level ofperformance is equivalent to young and age-unimpaired rats, indicatingthat treatment with 10 mg/kg/day levetiractam resulted in a significantrecovery of the AI rats' ability to navigate this MWM. The effectivnessof the 10 mg/kg/day levetiracetam treatment was also seen in the timespent in the target annulus (see FIG. 2).

Radial Arm Maze Results

The effects of levetiracetam on the spatial memory retention ofaged-impaired (AI) rats were assessed in a Radial Arm Maze (RAM)behavioral task using vehicle control and five different dosage levelsof levetiracetam (1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day, 10mg/kg/day and 20 mg/kg/day). RAM behavioral tasks were preformed on tenAI rats. All six treatment conditions were tested on all ten rats, asdescribed above for the MWM test.

The RAM apparatus used consisted of eight equidistantly-spaced arms. Anelevated maze arm (7 cm width×75 cm length) projected from each facet ofan octagonal center platform (30 cm diameter, 51.5 cm height). Clearside walls on the arms were 10 cm high and were angled at 65° to form atrough. A food well (4 cm diameter, 2 cm deep) was located at the distalend of each arm. Froot Loops™ (Kellogg Company) were used as rewards.Blocks constructed of Plexiglas™ (30 cm height×12 cm width) could bepositioned to prevent entry to any arm. Numerous extra maze cuessurrounding the apparatus were also provided.

The AI rats were initially subjected to a pre-training test (Chappell etal. Neuropharmacology 37: 481-487, 1998). The pre-training testconsisted of a habituation phase (4 days), a training phase on thestandard win-shift task (18 days) and another training phase (14 days)in which a brief delay was imposed between presentation of a subset ofarms designated by the experimenter (e.g., 5 arms available and 3 armsblocked) and completion of the eight-arm win-shift task (i.e., with alleight arms available).

In the habituation phase, rats were familiarized to the maze for an8-minute session on four consecutive days. In each of these sessionsfood rewards were scattered on the RAM, initially on the center platformand arms and then progressively confined to the arms. After thishabituation phase, a standard training protocol was used, in which afood pellet was located at the end of each arm. Rats received one trialeach day for 18 days. Each daily trial terminated when all eight foodpellets had been obtained or when either 16 choices were made or 15minutes had elapsed. After completion of this training phase, a secondtraining phase was carried out in which the memory demand was increasedby imposing a brief delay during the trial. At the beginning of eachtrial, three arms of the eight-arm maze were blocked. Rats were allowedto obtain food on the five arms to which access was permitted duringthis initial ‘information phase’ of the trial. Rats were then removedfrom the maze for 60 seconds, during which time the barriers on the mazewere removed, thus allowing access to all eight arms. Rats were thenplaced back onto the center platform and allowed to obtain the remainingfood rewards during this ‘retention test’ phase of the trial. Theidentity and configuration of the blocked arms varied across trials.

The number of “errors” the AI rats made during the retention test phasewas tracked. An error occurred in the trial if the rats entered an armfrom which food had already been retrieved in the pre-delay component ofthe trial, or if it re-visited an arm in the post-delay session that hadalready been visited.

After completion of the pre-training test, rats were subjected to trialswith more extended delay intervals, i.e., a one-hour delay, between theinformation phase (presentation with some blocked arms) and theretention test (presentation of all arms). During the delay interval,rats remained off to the side of the maze in the testing room, on cartsin their individual home cages. AI rats were pretreated 30-40 minutesbefore daily trials with a one-time shot of the following sixconditions: 1) vehicle control (0.9% saline solution); 2) levetiracetam(1.25 mg/kg/day); 3) levetiracetam (2.5 mg/kg/day); 4) levetiracetam (5mg/kg/day); 5) levetiracetam (10 mg/kg/day); 6) levetiracetam (20mg/kg/day); through intraperitoneal (i.p.) injection. Injections weregiven every other day with intervening washout days. Each AI rat wastreated with all six conditions within 23 days of testing. Tocounterbalance any potential bias, drug effect was assessed usingascending-descending dose series, i.e., the dose series was given firstin an ascending order and then repeated in a descending order.Therefore, each dose had two determinations.

Parametric statistics (paired t-tests) was used to compare the retentiontest performance of the AI rats in the one-hour delay version of the RAMtask in the context of different doses of levetiracetam and vehiclecontrol (see FIG. 3). The average numbers of errors that occurred in thetrials were also significantly fewer with levetiracetam treatment of 5mg/kg/day (average no. of errors±standard error of the mean(SEM)=0.75±0.32) and 10 mg/kg/day (average no. of errors±SEM=0.80±0.27)than using vehicle control (average no. of errors±SEM=2.00±0.42).Relative to vehicle control treatment, levetiracetam significantlyimproved memory performance at 5 mg/kg/day (t(9)=2.18, p=0.057) and 10mg/kg/day (t(9)=2.37, p=0.042).

The radial arm maze task was also used to evaluate the effect of acombination therapy with Levetiracetam (i.p. administration) andvalproate (subcutaneous administration). Levetiracetam, on its own, waseffective in reducing the number of errors by AI rats in the radial armmaze at 5-10 mg/kg doses, but not at 1.25 mg/kg or 2.5 mg/kg. Valproate,on its own, was effective at 100 mg/kg but not at 25 mg/kg or 50 mg/kg.See FIG. 4. Combining the two drugs, however, had a synergistic effect.A combined administration of 50 mg/kg valproate with 2.5 mg/kglevetiracetam, neither being an effective dose when administeredindividually, resulted in a reduced number of errors in the radial armmaze task. This result was also obtained at an even lower dose of 1.25mg/kg levetiracetam combined with 50 mg/kg valproate. See FIG. 5. Anisobologram of levetiracetam and valproate dosages confirmed that theeffect of the combined 50 mg/kg valproate and 1.25 mg/kg levetivacetam(VPA 50+LEV 1.25; empty circle) had a synergistic (super-additive)effect. The combined 50 mg/kg valproate and 2.5 mg/kg levetivacetam (VPA50+LEV 2.5; dark circle), on the other hand, had a simple additiveeffect, as indicated by its placement on the line. See FIG. 6.

To calculate the human equivalent dose (HED) for levetiracetam dosagefor treatment of age-dependent cognitive impairment in humans, weemployed the formula HED (mg/kg)=rat dose (mg/kg)×0.16 (see Estimatingthe Safe Starting Dose in Clinical Trials for Therapeutics in AdultHealthy Volunteers, December 2002, Center for Biologics Evaluation andResearch). Therefore, the dosage of 5 mg/kg/day in rats is equivalent to0.8 mg/kg/day in humans and the dosage of 10 mg/kg/day in rats isequivalent to 1.6 mg/kg/day in humans.

Example 3 Effect of Levetiracetam in Human Subjects with aMCI

A within-subjects trial of 8 weeks duration, involving 17 amnestic MCI(aMCI) subjects and 17 age-matched controls with a low dose treatment oflevetiracetam is conducted. During the course of the study, each aMCIsubject receives both drug and placebo treatments separately in twoperiods of two weeks each, with the order of treatments among differentaMCI subjects counterbalanced (see FIG. 7). Age-matched control subjectstreated with placebo serve as a further control. Cognitive testing andfMRI imaging data are obtained from the subjects after each two weekperiod of drug/placebo treatment.

Participants and Clinical Characterization

17 right-handed aMCI patients are recruited from the Alzheimer's DiseaseResearch Center (ADRC) at the Johns Hopkins Hospital and otherreferrals. An additional 17 right-handed healthy volunteers arerecruited from the pool of control participants in the ADRC and otherreferrals. All participants are administered the Telephone Interview ofCognitive Status to determine if they are likely to pass the entrycriteria of the study (including criteria for MRI scanning) Allparticipants further undergo neurological, psychiatric, andneuropsychological examination using standardized instruments andmethods. The psychiatric evaluation includes administration of theStructured Clinical Interview for DSM-IV Axis I Disorders and theClinical Dementia Rating (CDR) scale. All aMCI patients have CDR scoresof 0.5. Diagnosis of aMCI is based on the criteria proposed by Petersenet al. (e.g., “Mild cognitive impairment: Aging to Alzheimer's Disease,”Oxford University Press, N.Y. (2003), which include a memory complaint(corroborated by an informant), impaired memory function on testing (1.5standard deviations below norm), otherwise preserved cognitivefunctioning (within 1 standard deviation of norm), no decline infunctional ability, and no dementia. Final aMCI diagnoses are reached byclinical consensus. Exclusion criteria include major neurological orpsychiatric disorders, head trauma with loss of consciousness, historyof drug abuse or dependency, and general contraindications to an MRIexamination (e.g. cardiac pacemaker, aneurysm coils, claustrophobia).Each aMCI subject is required to have a study partner (i.e., aninformant) who can provide information about the subject's dailyfunction and assure that medications are taken appropriately. See FIGS.18A and 18B.

Study Visits:

The study consists of 4 visits over the course of 8 weeks (see FIG. 7).The Baseline Visit is for the purpose of performing medical,neurological, psychiatric, and neurocognitive assessments. Visits 1 and2 are identical to the Baseline Visit but include a fMRI session. TheWashout Visit, at the end of a 4 week washout period, is for the purposeof a brief clinical assessment and initiation of the second drug/placebophase.

Baseline Visit:

At the screening visit, informed consent is obtained from the subject(and an informant in the case of MCI subjects). The subject and theinformant participate in a standardized clinical interview that is usedto determine the degree of the subject's functional impairment in dailylife, based on the Clinical Dementia Rating (CDR) scale. The subject'smedical, neurological, and psychiatric history is obtained (including areview of current medications), as well as the family history ofdementia. Brief medical, neurological and psychiatric exams areconducted (including vital signs). Blood is drawn in order to performstandard laboratory tests needed to determine if the subject meets theentry criteria. The subject is re-screened for contraindications to MRIscanning, using the standard form employed at the Kirby Imaging Center.Brief cognitive testing is performed (described in section onneuropsychological assessment below). These assessments are used todetermine if the subject meets the entry criteria. All of the foregoingare completed using standardized forms. If the subject meets entrycriteria for the study, the subject is given the study medication (drugor placebo, randomly selected), and instructions about how it should betaken. The subject is advised about the potential for having suicidalthoughts and advised to stop taking the medication and immediatelycontact the study physician if this occurs.

Visit 1:

At the end of the first drug/placebo period 2 weeks after the BaselineVisit, the medical, neurological and psychiatric evaluations andcognitive testing are repeated. The subject is also clinically evaluatedfor suicidal ideation. Blood is drawn again to repeat the standard testsand to determine whether there are any changes related to drugtreatment; the subject's blood levetiracetam level is also obtained. Allmedication dispensed at the Baseline Visit (drug or placebo) iscollected and subject compliance with the medication regimen isassessed. The first fMRI session (with cognitive tests) is conducted onthe same day, either immediately before or immediately after theclinical assessment. Subjects discontinue first period treatment at thisvisit.

Washout Visit:

At the end of a washout period (4 weeks) following Visit 1, the subjectreceives a brief medical screening, including a medical and psychiatricevaluation. Blood is drawn to obtain the blood levetiracetam level (toconfirm washout). The subject is provided with new medication (drug orplacebo, alternated from what was assigned in the previous treatmentperiod) for the final phase of the study with instructions about how itshould be taken.

Visit 2:

At approximately 2 weeks after the Washout Visit (i.e., 2 weeks afterstarting the second treatment period), the medical, neurological andpsychiatric evaluations and the cognitive testing are repeated. Thesubject is clinically evaluated for suicidal ideation. Blood is drawnagain to repeat the standard tests and to determine whether there wereany changes related to drug treatment; the subject's blood levetiracetamlevel is also obtained. All medication dispensed at the Washout Visit iscollected and subject compliance with the medication regimen isassessed. The second fMRI session (with cognitive tests) is repeated onthe same day, either immediately before or immediately after theclinical assessment.

Neuropsychological Assessment

All participants undergo neuropsychological evaluation at the time ofassessment for treatment efficacy (Visits 1 and 2), as well as at theBaseline Visit. The evaluation occurs outside of the scanner andincludes the Buschke Selective Reminding Test (Buschke and Fuld, 1974)and the Verbal Paired Associates subtest, the Logical Memory subtest,the Visual Reproduction subtest of the Wechsler Memory Scale-Revised(WMS-R) (Wechsler, 1997), and the Benton Visual Retention Test, as thesetasks are particularly sensitive to medial temporal lobe function andearly memory problems (Marquis et al., 2002 and Masur et al., 1994).Additionally, subjects are asked to complete tests of more generalcognitive function such as tests to assess general mental status,executive function, attention and general naming ability. Allneuropsychological tests are administered by a trained researchassistant during a 60-minute session. As the three neuropsychologicalassessments in this study occur within a time period of 8 weeks,different versions of the neuropsychological tests are used to minimizetest specific practice effects. Breaks are provided to the subject asneeded.

Drug Administration

As described above, the drug treatment period is the two weeks precedingVisit 1 or 2 (with the two week period preceding the other Visit beingthe placebo phase). For the subjects receiving the drug treatment, halfa scored 250 mg tablet of levetiracetam is used to achieve a dose of 125mg twice a day, which is approximately 3.6 mg/kg/day (assuming anaverage adult human weight of 70 kg).

All drug and placebo preparations are performed on a 1:1 allocation. Thepharmacy randomizes patients to drug dose and condition as they enroll,and keep a list of drug assignment.

Levetiracetam is rapidly and almost completely absorbed after oraladministration, and its bioavailability is not affected by food. Plasmahalf-life of levetiracetam is approximately 7±1 hour (expected to be9-10 hours in elderly due to decreased renal function). Absorption israpid, with peak plasma concentrations occurring about 1 hour followingoral administration. Steady state can be achieved after 2 days ofmultiple twice-daily dosing.

A typical starting dose of levetiracetam in treating epilepsy in humansis 500 mg twice a day, which is approximately 14.3 mg/kg/day. The dosageis then is increased until optimal efficacy, up to 50 mg/kg/day. Thus,the dose used in this experiment is a quarter of the lowest human doseused for treating epilepsy.

Even lower dosages, e.g., of 25-60 mg twice a day, are contemplated,based on the results of previous animal studies that indicated low-doseefficacy. The highest effective doses of levetiracetam used in theanimal model are 5-10 mg/kg (given acutely). The human equivalent dose(HED), calculated as described above, of this dosage for treatment ofage-dependent cognitive impairment in humans is equivalent to 0.8-1.6mg/kg/day (or 28-56 mg twice a day).

MRI Data Acquisition

Imaging data are obtained through high-resolution methods developed inthe Stark laboratory. Data are collected on a Phillips 3 Tesla scanner(Eindhoven, The Netherlands) equipped with an 8-channel SENSE(Sensitivity Encoding) head coil, located at the F.M. Kirby ResearchCenter for Functional Brain Imaging at the Kennedy Krieger Institute(Baltimore, Md.). High-resolution echo-planar images are collected usingan acquisition matrix of 64×64, a repetition time of 1500 milliseconds,an echo time of 30 milliseconds, a flip angle of 70 degrees, a SENSEfactor of 2, and an isotropic resolution of 1.5 mm×1.5 mm x 1.5 mm withno gap. Nineteen oblique slices are acquired parallel to the principallongitudinal axis of the hippocampus and covered the entire medialtemporal lobe region bilaterally. In addition to the functional runs, awhole-brain MPRAGE structural scan (parameters: 150 oblique slices, 1 mmisotropic resolution) is acquired.

Image Analysis

Data analysis is carried out using the Analysis for FunctionalNeuroimages (AFNI, release 2008_(—)07_(—)18_(—)1710) software. Imagesare first co-registered to correct for within- and across-scan headmotion. Acquisitions in which a significant motion event occur (morethan 3 degrees of rotation or 2 mm of translation in any directionrelative to prior acquisition), plus and minus one time repetition for1.5 seconds, are excluded from the analyses. Structural anatomical dataare registered to standard stereotaxic space (Talairach & Tournoux,1988), and the same parameters are subsequently applied to thefunctional data. Behavioral vectors are produced to model differenttrial types.

The ROI-LDDMM (large deformation diffeomorphic metric mapping of theregion of interest) method, a technique for cross-subject alignment,increases the power of multisubject regional fMRI studies by focusingthe alignment power specifically on the ROIs (regions of interest) andnot elsewhere in the brain. First, all subjects' anatomical andfunctional scans are normalized to the Talairach atlas using AFNI.Sub-regions of the medial temporal lobe and the hippocampus (bilateralentorhinal cortex, perirhinal cortex, parahippocampal cortex,CA3/dentate region, CA1 region, and subiculum) are segmented in threedimensions on the MPRAGE scans. The labels for the CA3 region anddentate gyms (DG) are combined. The anatomically defined ROIs are thenused to calculate the ROI-LDDMM 3D vector field transformation for eachsubject using a customized template based on the mean of the entiresample tested as the target. The ROI-LDDMM transformations for eachindividual subject's ROIs are then applied to the fit coefficient maps.

Group data are analyzed using a two-way Analysis of Variance (ANOVA)with trial types and group as fixed factors, and subject as a randomfactor nested within group. A liberal peak threshold of p<0.05, alongwith a spatial extent threshold of 10 voxels are used to definefunctional ROIs on the overall F statistic. This approach, rather thanusing a direct pair-wise contrast, reduces voxel selection biasesbecause any differences amongst the various conditions allowed for avoxel to be selected. This threshold is then combined with theanatomical segmentations to only include voxels inside the regions ofinterest. This serves to exclude voxels that does not change with any ofthe model's factors, effectively limiting the analysis to voxels showingany changes with task condition or group. Voxels within each functionalROI are collapsed for further analysis.

Cognitive Tests During fMRI Scans at Visits 1 and 2

The activity of the subject's medial temporal lobe is measured byfunctional MRI during the subject's participation in an explicit3-alternative forced choice task, where participants view novel,repeated and similar (“lure”) stimuli. The Psychophysics Toolboxextensions in Matlab 7.0 (The MathWorks, Natick, Mass.) is used forstimulus presentation and behavioral data collection. Stimuli are colorphotographs of common objects. Each participant undergoes a series oftesting runs during the functional imaging sessions, each run consistingof a mix of three types of image pairs: similar pairs, identical pairsand unrelated foils. These image pairs are fully randomized throughoutthe run and presented individually as a series of images (see FIG. 10A).Participants are instructed to make a judgment as to whether each objectseen is new, old or similar. Of critical interest are the participants'responses when presented with the second of the pair of similar objects(the “lure”; see FIG. 10B). The correct identification by the subject oflure stimuli as “similar,” provides behavioral evidence of patternseparation, i.e., the separation of similar experiences into distinctnon-overlapping representations. However, an incorrect indentificationof lure stimuli as “old” or “new,” indicates a failure of patternseparation. Identification of lure stimuli as “old” indicates that thesubject focused on the similarities between the lure stimulus and theearlier-shown partner image. Identification of the lure stimulus as“new” indicates that the subject failed to recall the earlier-shownpartner image altogether. Each run also contains a number of baselinetrials that use a challenging perceptual discrimination task known toprovide a lower and more-stable estimate of baseline activity in themedial temporal lobe (Stark & Squire, 2001 PNAS; Law et al, 2005).

A survey of the activity level of various subregions in the medialtemporal lobe during the cognitive test, as measured by fMRI, shows thataMCI subjects have hyperactive DG/CA3 regions and a hypoactiveentorhinal cortex during the performance of memory tasks, compared toage-matched control subjects.

We assess the level of activity in DG/CA3 during successful memoryjudgments in control and aMCI subjects. The mean activity is calculatedfrom the average activity, as measured by fMRI, during the presentationof lure stimuli correctly identified by subject as “similar” that iscalibrated for baseline activity. FIG. 8A shows that aMCI patientsexhibit DG/CA3 hyperactivity when making these judgments (p=0.013). FIG.8B, however, shows that treatment with levetiracetam reduces DG/CA3hyper-activity in aMCI subjects (p=0.037). The activity level in theaMCI subject treated with the drug, in fact, is normalized to the extentthat that it is statistically indistinguishable from the activity ofcontrol subjects treated with placebo. See FIG. 8C for the mean activityvalues shown in FIGS. 8A and 8B.

The activity level during successful memory judgments in EC issignificantly lower in placebo-treated aMCI subjects compared tocontrols (p=0.003). See FIG. 9A. However, levetiracetam treatmentnormalizes activity in aMCI subjects in EC as well. See FIG. 9B.Levetiracetam treatment increases EC activity during memory judgments inaMCI subjects, such that it is statistically indistinguishable fromplacebo-treated control subjects. See FIG. 9B. See FIG. 9C for the meanactivity values shown in FIGS. 9A and 9B.

The normalization of DG/CA3 and EC activity during memory judgments bylevetiracetam treatment is mirrored in the change seen in the aMCIsubjects' performance in the cognitive task. With placebo treatment,aMCI patients perform worse than control subjects, correctly identifylure items as “similar” less often and incorrectly identifying them as“old” more often (p=0.009). See FIG. 11. However, the performance ofaMCI subjects improves significantly under levetiracetam treatment. SeeFIG. 12. The interaction of more correct “similar” indenficiations withless incorrect “old” identifications under drug treatment results in asignificant improvement in the performance of this memory task(p=0.039). See FIG. 13 for a table of the data represented in FIGS. 11and 12.

The performance of control-placebo subjects and aMCI subjects with drugor placebo treatment is also compared in other common cognitive tests,such as the Buschke Selective Reminding Test—Delayed Recall (FIGS. 14Aand 14B), the Benton Visual Rentention Test (FIGS. 15A and 15B), VerbalPaired Associates Test—Recognition (FIGS. 16A and 16B) and Verbal PairedAssociates Test—Delayed Recall (FIGS. 17A and 17B). In all of thesetests, aMCI subjects treated with placebo perform worse thanplacebo-treated control subjects, and levetiracetam treatment fail torescue performance in aMCI subjects.

There are a number of possible reasons why levetiracetam treatment doesnot help aMCI subjects with performance in these other cognitive tests.The explicit 3-alternative forced choice task done in the fMRI study isa task that is especially sensitive to DG/CA3 function. As such, theperformance of the subjects in this task may be particularly attuned tothe changes in DG/CA3 activity resulting from levetiracetam treatment.Further, the aMCI subjects were treated with levetiracetam for only twoweeks prior to the administration of the cognitive tests. It iscontemplated that a treatment duration of longer than two weeks, e.g.,16 weeks or 8 months, for the drug treatment will result in improvedefficacy. Finally, comparative animal studies (see Example 1) indicatethat an even lower dose would be more effective. The human dosage of 125mg twice a day is equivalent to a rat dosage of 22.3 mg/kg/day. As isshown in Example 2 and FIG. 3, 20 mg/kg levetiracetam is too high a dosein rats, and it fails to improve the performance of AI rats in theradial maze task. The effective doses of levetiracetam used in theanimal model are 5-10 mg/kg. The human equivalent dose (HED) of theoptimal rat dose is 0.8-1.6 mg/kg/day. Such a dosage would result in theadministration of 28-56 mg twice a day (which is substantially lowerthan the 125 mg twice a day used in this study). Thus, it iscontemplated that aMCI subjects will exhibit a further normalization ofDG/CA3 and EC activity, as well as further improved performance incognitive tests, if they are treated with lower doses equivalent to theeffective doses in rat, e.g., 25-60 mg twice a day of levetiracetam.

Example 4 Effect of Levetiracetam in Human Subjects with aMCI

A within-subjects trial of 8 weeks duration, involving 38 amnestic MCI(aMCI) subjects and 17 age-matched controls with a low dose treatment oflevetiracetam is conducted. During the course of the study, each aMCIsubject receives both drug and placebo treatments separately in twoperiods of two weeks each, with the order of treatments among differentaMCI subjects counterbalanced (see FIG. 7). Age-matched control subjectstreated with placebo serve as a further control. Cognitive testing andfMRI imaging data are obtained from the subjects after each two-weekperiod of drug/placebo treatment.

Participants and Clinical Characterization

38 right-handed aMCI patients are recruited from the Alzheimer's DiseaseResearch Center (ADRC) at the Johns Hopkins Hospital and otherreferrals. An additional 17 right-handed healthy volunteers arerecruited from the pool of control participants in the ADRC and otherreferrals. All participants are administered the Telephone Interview ofCognitive Status to determine if they are likely to pass the entrycriteria of the study (including criteria for MRI scanning) Allparticipants further undergo neurological, psychiatric, andneuropsychological examination using standardized instruments andmethods. The psychiatric evaluation includes administration of theStructured Clinical Interview for DSM-IV Axis I Disorders and theClinical Dementia Rating (CDR) scale. All aMCI patients have CDR scoresof 0.5. Diagnosis of aMCI is based on the criteria proposed by Petersenet al. (e.g., “Mild cognitive impairment: Aging to Alzheimer's Disease,”Oxford University Press, N.Y. (2003), which include a memory complaint(corroborated by an informant), impaired memory function on testing(generally 1.5 standard deviations below the norm and at least 1standard deviation below the norm), otherwise preserved cognitivefunctioning (within 1 standard deviation of norm), no decline infunctional ability, and no dementia. Final aMCI diagnoses are reached byclinical consensus. Exclusion criteria include major neurological orpsychiatric disorders, head trauma with loss of consciousness, historyof drug abuse or dependency, and general contraindications to an MRIexamination (e.g. cardiac pacemaker, aneurysm coils, claustrophobia).Each aMCI subject is required to have a study partner (i.e., aninformant) who can provide information about the subject's dailyfunction and assure that medications are taken appropriately.

Study Visits:

The study consists of 4 visits over the course of 8 weeks (see FIG. 7).The Baseline Visit is for the purpose of performing medical,neurological, psychiatric, and neurocognitive assessments. Visits 1 and2 are identical to the Baseline Visit but include an fMRI session. TheWashout Visit, at the end of a 4 week washout period, is for the purposeof a brief clinical assessment and initiation of the second drug/placebophase.

Baseline Visit:

At the screening visit, informed consent is obtained from the subject(and an informant in the case of MCI subjects). The subject and theinformant participate in a standardized clinical interview that is usedto determine the degree of the subject's functional impairment in dailylife, based on the Clinical Dementia Rating (CDR) scale. The subject'smedical, neurological, and psychiatric history is obtained (including areview of current medications), as well as the family history ofdementia. Brief medical, neurological and psychiatric exams areconducted (including vital signs). Blood is drawn in order to performstandard laboratory tests needed to determine if the subject meets theentry criteria. The subject is re-screened for contraindications to MRIscanning, using the standard form employed at the Kirby Imaging Center.Brief cognitive testing is performed (described in section onneuropsychological assessment below). These assessments are used todetermine if the subject meets the entry criteria. All of the foregoingare completed using standardized forms. If the subject meets entrycriteria for the study, the subject is randomly assigned to either the62.5 mg BID or 250 mg BID study group and given the study medication(drug or placebo, randomly selected), and instructions about how itshould be taken. The subject is advised about the potential for havingsuicidal thoughts and advised to stop taking the medication andimmediately contact the study physician if this occurs.

Visit 1:

At the end of the first drug/placebo period 2 weeks after the BaselineVisit, the medical, neurological and psychiatric evaluations andcognitive testing are repeated. The subject is also clinically evaluatedfor suicidal ideation. Blood is drawn again to repeat the standard testsand to determine whether there are any changes related to drugtreatment; the subject's blood levetiracetam level is also obtained. Allmedication dispensed at the Baseline Visit (drug or placebo) iscollected and subject compliance with the medication regimen isassessed. The first fMRI session (with cognitive tests) is conducted onthe same day, either immediately before or immediately after theclinical assessment. Subjects discontinue first period treatment at thisvisit.

Washout Visit:

At the end of a washout period (4 weeks) following Visit 1, the subjectreceives a brief medical screening, including a medical and psychiatricevaluation. Blood is drawn to obtain the blood levetiracetam level (toconfirm washout). The subject is provided with new medication (drug orplacebo, alternated from what was assigned in the previous treatmentperiod) for the final phase of the study with instructions about how itshould be taken.

Visit 2:

At approximately 2 weeks after the Washout Visit (i.e., 2 weeks afterstarting the second treatment period), the medical, neurological andpsychiatric evaluations and the cognitive testing are repeated. Thesubject is clinically evaluated for suicidal ideation. Blood is drawnagain to repeat the standard tests and to determine whether there wereany changes related to drug treatment; the subject's blood levetiracetamlevel is also obtained. All medication dispensed at the Washout Visit iscollected and subject compliance with the medication regimen isassessed. The second fMRI session (with cognitive tests) is repeated onthe same day, either immediately before or immediately after theclinical assessment.

Neuropsychological Assessment

All participants undergo neuropsychological evaluation at the time ofassessment for treatment efficacy (Visits 1 and 2), as well as at theBaseline Visit. The evaluation occurs outside of the scanner andincludes the Buschke Selective Reminding Test (Buschke and Fuld, 1974)and the Verbal Paired Associates subtest, the Logical Memory subtest,the Visual Reproduction subtest of the Wechsler Memory Scale-Revised(WMS-R) (Wechsler, 1997), and the Benton Visual Retention Test, as thesetasks are particularly sensitive to medial temporal lobe function andearly memory problems (Marquis et al., 2002 and Masur et al., 1994).Additionally, subjects are asked to complete tests of more generalcognitive function such as tests to assess general mental status,executive function, attention and general naming ability. Allneuropsychological tests are administered by a trained researchassistant during a 60-minute session. As the three neuropsychologicalassessments in this study occur within a time period of 8 weeks,different versions of the neuropsychological tests are used to minimizetest specific practice effects. Breaks are provided to the subject asneeded.

Drug Administration

As described above, the drug treatment period is the two weeks precedingVisit 1 or 2 (with the two week period preceding the other Visit beingthe placebo phase). For the subjects receiving the 250 mg BID (BIDstands for twice daily) drug treatment, two 250 mg tablets oflevetiracetam are used to achieve a dose of 250 mg twice a day, i.e.,500 mg/day, which is approximately 7.1 mg/kg/day (assuming an averageadult human weight of 70 kg). For the subjects receiving the 62.5 mg BIDdrug treatment, a quarter of a scored 250 mg tablet of levetiracetam isused to achieve a dose of 62.5 twice a day, i.e., 125 mg/day which isapproximately 1.5 mg/kg/day.

All drug and placebo preparations are performed on a 1:1 allocation. Thepharmacy randomizes patients to drug dose and condition as they enroll,and keep a list of drug assignment.

Levetiracetam is rapidly and almost completely absorbed after oraladministration, and its bioavailability is not affected by food. Plasmahalf-life of levetiracetam is approximately 7±1 hour (expected to be9-10 hours in elderly due to decreased renal function). Absorption israpid, with peak plasma concentrations occurring about 1 hour followingoral administration. Steady state can be achieved after 2 days ofmultiple twice-daily dosing.

A typical starting dose of levetiracetam in treating epilepsy in humansis 500 mg twice a day, which is approximately 14.3 mg/kg/day. The dosageis then is increased until optimal efficacy, up to 50 mg/kg/day. Thus,the 250 mg BID dose (500 mg/day) used in this experiment is one-half ofthe lowest human dose used for treating epilepsy. The 62.5 mg BID dose(125 mg/day) is one eighth of the lowest human dose used for treatingepilepsy.

MRI Data Acquisition

Imaging data are obtained through high-resolution methods developed inthe Stark laboratory. Data are collected on a Phillips 3 Tesla scanner(Eindhoven, The Netherlands) equipped with an 8-channel SENSE(Sensitivity Encoding) head coil, located at the F.M. Kirby ResearchCenter for Functional Brain Imaging at the Kennedy Krieger Institute(Baltimore, Md.). High-resolution echo-planar images are collected usingan acquisition matrix of 64×64, a repetition time of 1500 milliseconds,an echo time of 30 milliseconds, a flip angle of 70 degrees, a SENSEfactor of 2, and an isotropic resolution of 1.5 mm×1.5 mm x 1.5 mm withno gap. Nineteen oblique slices are acquired parallel to the principallongitudinal axis of the hippocampus and covered the entire medialtemporal lobe region bilaterally. In addition to the functional runs, awhole-brain MPRAGE structural scan (parameters: 231 oblique slices, 0.65mm isotropic resolution) is acquired.

Image Analysis

Data analysis is carried out using the Analysis for FunctionalNeuroimages (AFNI, release 2010_(—)10_(—)19_(—)1028) software. Imagesare first co-registered to correct for within- and across-scan headmotion. Acquisitions in which a significant motion event occur (morethan 3 degrees of rotation or 2 mm of translation in any directionrelative to prior acquisition), plus and minus one time repetition for1.5 seconds, are excluded from the analyses. Structural anatomical dataare registered to standard stereotaxic space (Talairach & Tournoux,1988), and the same parameters are subsequently applied to thefunctional data. Behavioral vectors are produced to model differenttrial types.

The ROI-LDDMM (large deformation diffeomorphic metric mapping of theregion of interest) method, a technique for cross-subject alignment,increases the power of multisubject regional fMRI studies by focusingthe alignment power specifically on the ROIs (regions of interest) andnot elsewhere in the brain. First, all subjects' anatomical andfunctional scans are normalized to the Talairach atlas using AFNI.Sub-regions of the medial temporal lobe and the hippocampus (bilateralentorhinal cortex, perirhinal cortex, parahippocampal cortex,CA3/dentate region, CA1 region, and subiculum) are segmented in threedimensions on the MPRAGE scans. The labels for the CA3 region anddentate gyms (DG) are combined. The anatomically defined ROIs are thenused to calculate the vector field transformation for each subject usingthe Advanced Normalization Tools (ANTs) software package and acustomized template based on the mean of the entire sample tested as thetarget. The resulting vector transformations for each individualsubject's ROIs are then applied to the fit coefficient maps.

Group data are analyzed using a two-way Analysis of Variance (ANOVA)with trial types and group as fixed factors, and subject as a randomfactor nested within group. A liberal peak threshold of p<0.07, alongwith a spatial extent threshold of 40 voxels are used to definefunctional ROIs on the overall F statistic. This approach, rather thanusing a direct pair-wise contrast, reduces voxel selection biasesbecause any differences amongst the various conditions allowed for avoxel to be selected. This threshold is then combined with theanatomical segmentations to only include voxels inside the regions ofinterest. This serves to exclude voxels that does not change with any ofthe model's factors, effectively limiting the analysis to voxels showingany changes with task condition or group. Voxels within each functionalROI are collapsed for further analysis.

Cognitive Tests During fMRI Scans at Visits 1 and 2

The activity of the subject's medial temporal lobe is measured byfunctional MRI during the subject's participation in an explicit3-alternative forced choice task, where participants view novel,repeated and similar (“lure”) stimuli. The Psychophysics Toolboxextensions in Matlab 7.0 (The MathWorks, Natick, Mass.) is used forstimulus presentation and behavioral data collection. Stimuli are colorphotographs of common objects. Each participant undergoes a series oftesting runs during the functional imaging sessions, each run consistingof a mix of three types of image pairs: similar pairs, identical pairsand unrelated foils. These image pairs are fully randomized throughoutthe run and presented individually as a series of images (see FIG. 10A).Participants are instructed to make a judgment as to whether each objectseen is new, old or similar. Of critical interest are the participants'responses when presented with the second of the pair of similar objects(the “lure”; see FIG. 10B). The correct identification by the subject oflure stimuli as “similar,” provides behavioral evidence of patternseparation, i.e., the separation of similar experiences into distinctnon-overlapping representations. However, an incorrect identification oflure stimuli as “old” or “new,” indicates a failure of patternseparation. Identification of lure stimuli as “old” indicates that thesubject focused on the similarities between the lure stimulus and theearlier-shown partner image. Identification of the lure stimulus as“new” indicates that the subject failed to recall the earlier-shownpartner image altogether. Each run also contains a number of baselinetrials that use a challenging perceptual discrimination task known toprovide a lower and more-stable estimate of baseline activity in themedial temporal lobe (Stark & Squire, 2001 PNAS; Law et al, 2005).

A survey of the activity level of various subregions in the medialtemporal lobe during the cognitive test, as measured by fMRI, shows thataMCI subjects have hyperactive DG/CA3 regions and a hypoactiveentorhinal cortex during the performance of memory tasks, compared toage-matched control subjects.

We assess the level of activity in DG/CA3 during successful memoryjudgments in control and aMCI subjects. The mean activity is calculatedfrom the average activity, as measured by fMRI, during the presentationof lure stimuli correctly identified by subject as “similar” that iscalibrated for baseline activity. FIGS. 22A and 22B show that aMCIpatients in both the 62.5 mg BID cohort (N=20) and 250 mg BID cohort(N=17) exhibit DG/CA3 hyperactivity when making these judgments(p=0.0041 and p=0.0466 respectively). Treatment with levetiracetam doesnot significantly reduce the DG/CA3 hyperactivity in aMCI subjects inthe 250 mg BID or the 62.5 mg BID cohort.

The level of DG/CA3 activity during memory judgments by levetiracetamtreatment is mirrored in the change seen in the aMCI subjects'performance in the cognitive task. With placebo treatment, aMCI patientsperform worse than control subjects, correctly identify lure items as“similar” less often and incorrectly identifying them as “old” moreoften in both the 62.5 mg BID cohort and the 250 mg BID cohort. SeeFIGS. 23A and 23B. However, the performance of aMCI subjects improvessignificantly under 62.5 mg BID levetiracetam treatment. See FIG. 24A.The interaction of more correct “similar” identifications with lessincorrect “old” identifications under drug treatment results in asignificant improvement in the performance of this memory task(p=0.041). The performance of aMCI subjects does not significantlyimprove under 250 mg BID levetiracetam treatment (p=0.2396). See FIG.24B.

Example 5 Effect of Brivaracetam and Seletractam in Aged-Impaired Rats

Subjects

Aged, male Long-Evans rats were obtained at 8-9 month of age fromCharles River Laboratories (Raleigh, N.C.) and housed in a vivarium atJohns Hopkins University until 24-26 month of age. Young rats obtainedfrom the same source were housed in the same vivarium and tested at 6month of age. All rats were individually housed at 25° C. and maintainedon a 12 hr light/dark cycle. Food and water were provided ad libitumunless noted otherwise. The rats were examined for health andpathogen-free status throughout the experiments, as well as necropsiesat the time of sacrifice. All procedures in the current investigationswere approved by the Institutional Animal Care and Use Committee inaccordance with the National Institutes of Health directive.

Background Characterization of Cognitive Status

All rats were screened in a standardized assessment of spatial cognitionprior to the studies with experimental treatments. That backgroundassessment used a well-established Morris Water Maze protocol. The MWMprotocol was substantially the same as the one described in Example 1.See, also, Gallagher et al., Behav. Neurosci. 107:618-626, (1993).Briefly, the rats were trained for eight days (three trials per day) tolocate a camouflaged escape platform that remained at the same locationthroughout training in a water maze. Every sixth trial consisted of aprobe trial (free swim with no escape platform) that served to assessthe development of a spatially localized search for the escape platform.During these probe trials, a learning index was generated from theproximity of the rat to the escape platform and was used to defineimpairment in the aged rats. The learning index is the sum of weightedproximity scores obtained during probe trials, with low scoresreflecting a search near the escape platform and high scores reflectingsearches farther away from the platform (Gallagher et al, 1993). Cuetraining (visible escape platform) occurred on the last day of trainingto test for sensorimotor and motivational factors independent of spatiallearning. Aged rats with impaired spatial memory performance (i.e.,those with learning index scores outside the young “normative” range)but successful cued training performance were characterized asAged-Impaired rats (i.e., AI rats). The AI rats were used for thestudies as described below.

Treatments

The radial arm maze experiments used acute administration ofseletracetam (0-4 mg/kg), brivaracetam (0-4 mg/kg), or saline vehiclegiven by intraperitoneal injection (in a volume of 1 ml/kg) 30-40 minprior to test sessions. In the chronic treatment experiment,memory-impaired aged rats were implanted subcutaneously in theintrascapular region with osmotic mini-pumps (ALZET, Durect Corporation,Cupertino, Calif.) with brivaracetam (2 mg/kg/day) or saline vehiclestarting two weeks prior to assessment in the water maze.

Behavioral Assessment in the Radial Arm Maze

A radial arm maze (RAM) task was used to assess effects of acute drugtreatment with seletracetam and brivaracetam. This protocol allowedwithin-subject assessment across drugs at different doses. The radialmaze consisted of eight arms projecting from each side of an octagonalcenter platform, with a food well located at the distal end of each arm.Plexiglas blocks could be positioned to prevent entry into any arm.Extra-maze cues were provided in the room surrounding the maze andillumination was provided by an overhead light.

Pre-training, as described in detail in Chappell et al.Neuropharmacology 37: 481-487, (1998), consisted of habituation,standard win-shift training, and win-shift training with delaysinterposed between information and memory test phases. Drug treatmentsbegan two days after the completion of pre-training Three arms wereblocked at the beginning of each trial (information phase). The identityand configuration of the blocked arms were varied across trials.Food-deprived rats were allowed to retrieve food reward (Kellogg's FrootLoops cereal) from the five unblocked arms. The rat was then removedfrom the maze for 2 hr (retention interval), during which time thebarriers on the blocked arms were removed allowing access to all eightarms. Rats were then placed back onto the center platform and allowed toretrieve the remaining food rewards (memory test phase). An errorconsisted of returning to an arm (all four paws on the arm) from whichfood had already been obtained. Memory-impaired aged rats (n=8 forseletracetam, and n=9 for brivaracetam) were first tested with a seriesof drug doses in ascending/descending order; each dose was thus testedtwice, with one washout day in between each determination. The number oferrors made in the retention phase after the 2-hr delay was used toassess memory performance. See FIG. 19 and FIG. 20. A series ofdifferent doses of brivaracetam was tested: 0.0625 mg/kg, 0.125 mg/kg,0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg. A series ofdifferent doses of seletracetam was tested: 0.0625 mg/kg, 0.125 mg/kg,0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg and 4 mg/kg. As shown in FIG.19, brivaracetam has a significant effect as a function of dose in therange tested (repeated measures ANOVA for within-subject contrasts, F(1,8)=6.046, p=0.039). As shown in FIG. 20, seletracetam also has asignificant effect as a function of dose in the range tested (repeatedmeasures ANOVA for within-subject contrasts, F(1, 7)=12.577, p=0.009).

Behavioral Assessment in the Water Maze

Rats were trained and tested in a novel water maze environment to assessthe effect of drug treatment. The water maze used here was housed in adifferent building and was surrounded by curtains with a novel set ofpatterns relative to the maze used for initial assessment of cognitivestatus. The training protocol consisted of 6 trials per day for 2 daysto locate a submerged escape platform. On each trial, a rat was releasedin the maze from one of four equally spaced starting positions aroundthe perimeter of the pool. The starting position varied from trial totrial. If the rat did not locate the escape platform within 60 s on anytrial, the experimenter guided and placed the rat on the platform, whereit remained for 20 s. The rat was then removed from the platform andplaced in a holding cage for another 40 s before the next trial.Approximately 24 hr after the last training trial, a probe test in theabsence of the escape platform was given to assess spatial memory.Results of the behavior assessment in the Water Maze task were shown inFIG. 21A and FIG. 21B. Rats treated with brivaracetam at 2 mg/kg/day(t(2)=10.000, p=0.010) but not vehicle (t(2)=1.964, p=0.188) showed asignificant spatial bias for the target quadrant compared to the othercontrols quadrants. In addition, brivaracetam-treated rats (2 mg/kg/day)spent significantly more time in the target quadrant than thevehicle-treated rats, t(4)=3.881, p=0.018. Brivaracetam-treated rats (2mg/kg/day) spent significantly more time in the target annulus (areasurrounding the location of the escape platform) than thevehicle-treated rats, t(4)=3.109, p=0.036.

Example 6 Chronic Treatment with Levetiracetam in Aged-Impaired Rats

Subjects

Aged, male Long-Evans rats were obtained at 8-9 month of age fromCharles River Laboratories (Raleigh, N.C.) and housed in a vivarium atJohns Hopkins University until 24-26 month of age. Young rats obtainedfrom the same source were housed in the same vivarium and tested at 6month of age. All rats were individually housed at 25° C. and maintainedon a 12 hr light/dark cycle. Food and water were provided ad libitumunless noted otherwise. The rats were examined for health andpathogen-free status throughout the experiments, as well as necropsiesat the time of sacrifice. All procedures in the current investigationswere approved by the Institutional Animal Care and Use Committee inaccordance with the National Institutes of Health directive.

Background Behavioral Characterization

All rats were screened in a standardized assessment of spatial cognitionprior to the studies with experimental treatments. That backgroundassessment used a well-established Morris water maze protocol asdescribed in Gallagher et al, 1993. Briefly, the rats were trained foreight days (three trials per day) to locate a camouflaged escapeplatform that remained at the same location throughout training in awater maze. Every sixth trial consisted of a probe trial (free swim withno escape platform) that served to assess the development of a spatiallylocalized search for the escape platform. During these probe trials, alearning index was generated from the proximity of the rat to the escapeplatform and was used to define impairment in the aged rats. Thelearning index is the sum of weighted proximity scores obtained duringprobe trials, with low scores reflecting a search near the escapeplatform and high scores reflecting searches farther away from theplatform (Gallagher et al, 1993). Cue training (visible escape platform)occurred on the last day of training to test for sensorimotor andmotivational factors independent of spatial learning. Aged rats withimpaired spatial memory performance (i.e., those with learning indexscores outside the young “normative” range) but successful cued trainingperformance were used for the studies as described below.

Surgery and Treatments

Under isoflurane anesthesia, memory-impaired aged rats were implantedsubcutaneously in the intrascapular region with osmotic mini-pumps(ALZET, Durect Corporation, Cupertino, Calif.) with levetiracetam (10mg/kg/day) or saline vehicle for four weeks prior to perfusion. Youngrats, which served as controls, received either saline vehicle inmini-pumps or no implantation.

Perfusion and Tissue Preparation

At the end of the 4-week treatment period, rats were anesthetized withisoflurane and perfused transcardiacally with 0.1 M phosphate buffersaline, followed by 4% paraformaldehyde in phosphate buffer. Brains wereremoved and post-fixed in paraformaldehyde overnight. The brains werethen moved into 4% paraformaldehyde in phosphate buffer containing 16%sucrose. The brains were then sectioned with a freezing microtome on thecoronal plane at 40 μm and stored in either 4% paraformaldehyde at 4° C.for in situ hybridization or cryoprotectant at −20° C. forimmunohistochemistry.

Probe Synthesis

Probe templates were synthesized as described in Haberman et al. (2008).Initial primer sequences for reelin were as follows: left,agtactcagacgtgcagtgg, right, ctcatgaagcaaagtccaa; PCR products wereverified by restriction endonuclease digestion. Initial PCR productswere amplified further with the same PCR primers that had been modifiedby the addition of T7 or SP6 RNA polymerase binding sites. PCR productscontaining T7 and SP6 extensions were purified by SVgel and a PCRcleanup kit (Promega). 35S-UTP labeled riboprobe was then generatedusing the Maxiscript kit (Ambion). The probe was then phenol/choloroformextracted and precipitated in ethanol at −80° C. The final probe wasresuspended in RNase-free water and the specific activity was determinedby scintillation counter.

In Situ Hybridization

In situ hybridization was carried out as described by Haberman et al.,(2008). Free-floating tissue sections were washed in 0.75% glycine in0.1M phosphate buffer two times, followed by a single wash in phosphatebuffer. After that, sections were reacted in Proteinase K buffercontaining 1.0 μg/ml proteinase K for 30 minutes at 37° C. Sections werethen treated with acetic anhydride solution (11.3% triethanolamine,0.25% acetic anhydride, 0.04 M acetic acid) for 10 minutes at roomtemperature. This was followed by two 15-minute washes in 2× sodiumchloride/citrate buffer (SSC buffer; 20× concentration, 3M NaCl, 0.3Msodium citrate). Next, sections were transferred to hybridization buffercontaining 20% formamide, 0.4×Denhardt's solution, 4% dextran sulfate,and 1.6×SSC) supplemented with 0.25 mg/ml tRNA, 0.33 mg/ml shearedsalmon sperm DNA, 100 mM DTT, and 1×107 cpm/ml 35S-UTP-labeled probe forovernight reaction at 60° C. The following day, sections were washed at60° C. in 4×SSC/0.01M DTT and 2×SSC/50% formamide. They were thenincubated with RNase (20 μg/ml) at 37° C. for 30 min. Sections werewashed with progressively decreasing concentrations of SSC beforemounting on slides. Slides were dried overnight, exposed to aphosphoimager screen, and quantified by using ImageQuant (GEHealthcare). Digital images were acquired of entorhinal corticalsections from the same levels for all animals and the subregion ofinterest was outlined and quantified. Sections were averaged to obtain asingle score for each animal.

Immunohistochemistry

Tissue was labeled with anti-SOM antiserum (Santa Cruz Biotechnology;cat. no. SC7819-P) using an established immunoperoxidase protocol andtissue sections were processed concurrently to minimizeinter-replication variability (Haberman et al., 2009). The anti-SOMantiserum can detect somatostatin. Briefly, sections were washed in 0.1Mphosphate-buffered saline (PBS) to remove cryoprotectant, and endogenousperoxidases were quenched in 0.3% H202 in PBS. After additional PBSwashes, sections were blocked in 5% normal horse serum in PBS with 0.3%Triton. Sections were then incubated with primary antibody at a dilutionof 1:1600 in PBS containing 0.15% Triton and 3% normal serum for 72hours at 4° C. with agitation. Following primary antibody incubation,sections were washed in PBS and reacted with horse anti-goat IgGbiotinylated secondary antibody (Vector Laboratories Inc., Burlingame,Calif.) diluted in PBS with 0.15% Triton and 5% normal horse serum for45 minutes. The secondary antibody was detected with avidin-biotincomplex (ABC Elite; Vector Laboratories Inc., Burlingame, Calif.) andthe avidin-biotin complex was visualized with nickel-enhanceddiaminobenzadine (Vector Laboratories Inc., Burlingame, Calif.). Tissuesections were mounted onto coated slides and dried, dehydrated withincreasing concentrations of ethanol, cleared with xylene, andcoverslipped using DPX mounting media.

Interneuron quantification was performed using a Zeiss Axioplan 2microscope equipped with a motorized stage. All analyses were conductedblind with regards to animal age and cognitive status. The dentate hilarregion was defined using the Paxinos and Watson rat brain atlas (1998).Dorsal hilar neuron counts were derived bilaterally from four matchedtissue sections per animal with a 40× objective lens (Bregma −3.80 mm to−4.16 mm). Neuron counts were analyzed as the total number of hilarinterneurons per hippocampal section for each rat.

Results

Somatostatin is a peptide hormone that regulates the endocrine systemand affects neurotransmission and cell proliferation via interactionwith G protein-coupled somatostatin receptors and inhibition of therelease of numerous secondary hormones. Somatostatin levels in the brainhave been shown to drop as low as 10-20% in association with aging andAlzheimer's disease progression. A four-week treatment withlevetiracetam at a dose of 10 mg/kg/day in aged-impaired rats restoresthe levels of somatostatin in DG hilus. See FIG. 25. Aged-impaired ratsthat were administered a saline vehicle rather than drug possessedsignificantly lower numbers of SOM-immunoreactive hilar neurons relativeto both young and levetiracetam treated aged rats (N=18; F2,20=15.739,p<0.001; AI-LEV vs Y, p=0.679; AI-LEV vs AI-VEH, p<0.01; AI-VEH vs Y,p<0.001).

Reelin is a large secreted extracellular matrix glycoprotein that helpsregulate processes of neuronal migration and positioning in thedeveloping brain by controlling cell-cell interactions. Reduced reelinexpression in EC2 neurons has been observed in aged rats with memoryloss, in hAPPJ20 AD mice, as well as in human AD brains (Chin et al.2007; Stranahan et al. 2010). A four-week treatment with levetiracetamat a dose of 10 mg/kg/day in aged-impaired rats restores the levels ofreelin in Entorhinal Cortex (EC2). See FIG. 26. A one-way ANOVA shows asignificant difference among the groups, F(2, 20)=5.035, p=0.017.Additional analysis shows that reelin mRNA expression in the lateralentorhinal cortex of AI rats treated with vehicle controls (AI-VEH) issignificantly lower than that of young rats, t(13)=2.790, p=0.015.Treatment with levetiracetam in AI rats at a dose of 10 mg/kg/day for 28days (AI-LEV) significantly increased the expression of reelin,t(13)=2.386, p=0.033 (compared to AI-VEH).

Example 7 Evaluation of Levetiracetam Blood Plasma Levels

Human: in the human studies described in Examples 3 and 4, a subject'slevetiracetam blood plasma level was assessed at each visit. Thesubject's blood was drawn by the Johns Hopkins Phlebotomy Service andanalysis of levetiracetam blood plasma levels was conducted either bythe Johns Hopkins Core laboratory or by MedTox Laboratories in St. Paul,Minn. for the 62.5 mg BID cohort, the 125 mg BID cohort and the 250 mgBID cohort. Upon completion of the levetiracetam treatment, subjects inthe 62.5 mg BID cohort showed a mean levetiracetam blood plasma level of2.88 mcg/ml (SEM±0.288), while levels in the 125 mg BID had 4.4 mcg/ml(SEM±0.53) and subjects in the 250 mg BID cohort showed meanlevetiracetam blood plasma level of 7.9 mcg/ml (SEM±0.92). See FIGS.27A-27C.

Rats: Blood was drawn from aged-impaired rats by cardiac puncture duringperfusion after a 28-day levetiracetam treatment period and sent foranalysis of levetiracetam plasma levels by MedTox Laboratories in St.Paul, Minn. Aged-impaired rats treated with 10 mg/kg/day oflevetiracetam showed a mean levetiracetam blood plasma level of 3.8mcg/ml (SEM±0.255), while those treated with 60 mg/kg/day showed a meanlevetiracetam blood plasma level of 22.4 mcg/ml (SEM±3.371).

What is claimed is:
 1. A method for treating cognitive impairmentassociated with a central nervous system (CNS) disorder in a subject inneed or at risk thereof, delaying or slowing the progression ofcognitive impairment, or reducing the rate of decline of cognitivefunction in the subject, the method comprising the step of administeringto said subject a therapeutically effective amount of a synaptic vesicleprotein 2A (SV2A) inhibitor or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof.
 2. The method of claim1, wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is selected from thegroup of SV2A inhibitors referred to in International Patent ApplicationPCT/US2009/005647; International Patent Application PublicationsWO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595;WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658;WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549; 7,244,747;5,334,720; 4,696,943; 4,696,942; U.S. patent application Ser. Nos.12/580,464; 61/105,847; 61/152,631; and 61/175,536; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692; orpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof.
 3. The method of claim 1, wherein the SV2A inhibitoror the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is selected from the group consisting of levetiracetam,seletracetam, and brivaracetam or pharmaceutically acceptable salts,hydrates, solvates, polymorphs, or prodrugs thereof.
 4. The method ofclaim 1, wherein the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof is levetiracetamor a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof.
 5. The method of claim 1, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is brivaracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof.
 6. The method of claim1, wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is seletracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof.
 7. The method of any one of claims 1 to 6, wherein theSV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is administered at a daily doseof 0.1 mg/kg to 5 mg/kg.
 8. The method of claim 7, wherein the dailydose is 0.1-0.2 mg/kg.
 9. The method of any one of claims 1 to 6,wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 0.01 mg/kg to 2.5 mg/kg.
 10. The method of claim 9,wherein the daily dose is 0.1-2.5 mg/kg.
 11. The method of claim 9,wherein the daily dose is 0.4-2.5 mg/kg.
 12. The method of claim 9,wherein the daily dose is 0.6-1.5 mg/kg.
 13. The method of claim 9,wherein the daily dose is 0.04-2.5 mg/kg.
 14. The method of claim 9,wherein the daily dose is 0.06-1.5 mg/kg.
 15. The method of any one ofclaims 1 to 6, wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 2 mg/kg to 4 mg/kg.
 16. The method ofclaim 15, wherein the daily dose is 2-3 mg/kg.
 17. The method of claim15, wherein the daily dose is 3-4 mg/kg.
 18. The method of any one ofclaims 1 to 6, wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.2 mg/kg to 0.4 mg/kg.
 19. The methodof claim 18, wherein the daily dose is 0.2-0.3 mg/kg.
 20. The method ofclaim 18, wherein the daily dose is 0.3-0.4 mg/kg.
 21. The method of anyone of claims 1 to 6, wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.001-5 mg/kg.
 22. The method of claim21, wherein the daily dose is 0.001-0.5 mg/kg.
 23. The method of claim21, wherein the daily dose is 0.01-0.5 mg/kg.
 24. The method of any oneof claims 1 to 6, wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.0015-7 mg/kg.
 25. The method of claim24, wherein the daily dose is 0.0015-5 mg/kg.
 26. The method of claim24, wherein the daily dose is 0.01-5 mg/kg.
 27. The method of claim 24,wherein the daily dose is 0.05-4 mg/kg.
 28. The method of claim 24,wherein the daily dose is 0.05-2 mg/kg.
 29. The method of claim 24,wherein the daily dose is 0.05-1.5 mg/kg.
 30. The method of claim 24,wherein the daily dose is 0.1-1 mg/kg.
 31. The method of claim 24,wherein the daily dose is 1-5 mg/kg.
 32. The method of claim 24, whereinthe daily dose is 1.5-4 mg/kg.
 33. The method of claim 24, wherein thedaily dose is 1.5-3.6 mg/kg.
 34. The method of any one of claims 1-33,wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered in anextended release form, a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form.
 35. The method of any one of claims 1-33, wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered twice a day.
 36. Themethod of any one of claims 1-34, wherein the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered once daily.
 37. A method for treatingcognitive impairment associated with a central nervous system (CNS)disorder in a subject in need or at risk thereof, delaying or slowingthe progression of cognitive impairment in the subject, or reducing therate of decline of cognitive function in the subject, the methodcomprising the step of administering to said subject an SV2A inhibitoror a pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in combination with valproate or a derivative, analog,pharmaceutically acceptable salt, hydrate, solvate, or polymorph orprodrug thereof.
 38. The method of claim 37, wherein the valproate orthe derivative, analog, pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof is administered at a daily dosesuch that the subject maintains a blood total valproate level of 0.5 to5 μg/ml plasma, and wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of less than 7 mg/kg, less than 6 mg/kg,less than 5 mg/kg, less than 4 mg/kg, less than 3.6 mg/kg, less than 3mg/kg, less than 2 mg/kg, less than 1.5 mg/kg, less than 1.5 mg/kg, lessthan 1 mg/kg, less than 0.1 mg/kg, less than 0.05 mg/kg, less than 0.01mg/kg, or less than 0.0015 mg/kg.
 39. The method of claim 37, whereinthe valproate or the derivative, analog, pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug thereof is administered ata daily dose such that the subject maintains a blood total valproatelevel of 0.5 to 5 μg/ml plasma, and wherein the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 0.01 to 1 mg/kg. 40.The method of claim 37, wherein the valproate or the derivative, analog,pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof is administered at a daily dose such that the subject maintainsa blood total valproate level of 0.5 to 5 μg/ml plasma, and wherein theSV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is administered at a daily doseof 0.001 to 1 mg/kg.
 41. The method of claim 37, wherein the valproateor the derivative, analog, pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof is administered at a daily dosesuch that the subject maintains a blood total valproate level of 0.5 to5 μg/ml plasma, and wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.1 to 5 mg/kg.
 42. The method of claim37, wherein the valproate or the derivative, analog, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug thereof isadministered at a daily dose such that the subject maintains a bloodtotal valproate level of 0.5 to 5 μg/ml plasma, and wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 0.05 to0.5 mg/kg.
 43. The method of claim 37, wherein the valproate or thederivative, analog, pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof is administered at a daily dose such thatthe subject maintains a blood total valproate level of 0.5 to 5 μg/mlplasma, and wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.001 to 5 mg/kg.
 44. The method ofclaim 37, wherein the valproate or the derivative, analog,pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof is administered at a daily dose such that the subject maintainsa blood total valproate level of 0.5 to 5 μg/ml plasma, and wherein theSV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is administered at a daily doseof 0.0015 to 5 mg/kg.
 45. The method of claim 37, wherein the valproateor the derivative, analog, pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof is administered at a daily dosesuch that the subject maintains a blood total valproate level of 0.5 to5 μg/ml plasma, and wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.01 to 5 mg/kg.
 46. The method of claim37, wherein the valproate or the derivative, analog, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug thereof isadministered at a daily dose such that the subject maintains a bloodtotal valproate level of 0.5 to 5 μg/ml plasma, and wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 0.05 to4 mg/kg.
 47. The method of claim 37, wherein the valproate or thederivative, analog, pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof is administered at a daily dose such thatthe subject maintains a blood total valproate level of 0.5 to 5 μg/mlplasma, and wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.05 to 2 mg/kg.
 48. The method of claim37, wherein the valproate or the derivative, analog, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug thereof isadministered at a daily dose such that the subject maintains a bloodtotal valproate level of 0.5 to 5 μg/ml plasma, and wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 0.05 to1.5 mg/kg.
 49. The method of claim 37, wherein the valproate or thederivative, analog, pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof is administered at a daily dose such thatthe subject maintains a blood total valproate level of 0.5 to 5 μg/mlplasma, and wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.1 to 1.0 mg/kg.
 50. The method ofclaim 37, wherein the valproate or the derivative, analog,pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof is administered at a daily dose such that the subject maintainsa blood total valproate level of 0.5 to 5 μg/ml plasma, and wherein theSV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is administered at a daily doseof 1 to 5 mg/kg.
 51. The method of claim 37, wherein the valproate orthe derivative, analog, pharmaceutically acceptable salt, hydrate,solvate, polymorph or prodrug thereof is administered at a daily dosesuch that the subject maintains a blood total valproate level of 0.5 to5 μg/ml plasma, and wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 1.5 to 4 mg/kg.
 52. The method of claim37, wherein the valproate or the derivative, analog, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug thereof isadministered at a daily dose such that the subject maintains a bloodtotal valproate level of 0.5 to 5 μg/ml plasma, and wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 1.8 to3.6 mg/kg.
 53. The method of any one of claims 37 to 52, wherein theSV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is selected from the group ofSV2A inhibitors referred to in International Patent ApplicationPCT/US2009/005647; International Patent Application PublicationsWO2010/144712; WO2010/002869; WO2008/132139; WO2007/065595;WO2006/128693; WO2006/128692; WO2005/054188; WO2004/087658;WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465,549; 7,244,747;5,334,720; 4,696,943; 4,696,942; U.S. patent application Ser. Nos.12/580,464; 61/105,847; 61/152,631; and 61/175,536; U.S. PatentApplication Publication Numbers 20090312333; 20090018148; 20080081832;2006258704; and UK Patent Numbers 1,039,113; and 1,309,692; orpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof.
 54. The method of any one of claims 37 to 52, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is selected from the groupconsisting of levetiracetam, seletracetam, and brivaracetam orpharmaceutically acceptable salts, hydrates, solvates, polymorphs, orprodrugs thereof.
 55. The method of any one of claims 37 to 52, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is levetiracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof.
 56. The method of any one of claims 37 to 52, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is brivaracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof.
 57. The method of any one of claims 37 to 52, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is seletracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof.
 58. The method of any one of claims 37 to 57, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof and the valproate or thederivative, analog, pharmaceutically acceptable salt, hydrate, solvate,polymorph or prodrug thereof are administered simultaneously.
 59. Themethod of any one of claims 37 to 57, wherein the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and the valproate or the derivative, analog,pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof are administered in a single formulation.
 60. The method of anyone of claims 37 to 57, wherein the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and the valproate or the derivative, analog,pharmaceutically acceptable salt, hydrate, solvate, polymorph or prodrugthereof are administered sequentially.
 61. The method of any one ofclaims 37 to 57, wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof and thevalproate or the derivative, analog, pharmaceutically acceptable salt,hydrate, solvate, polymorph or prodrug thereof are administered inseparate formulation.
 62. The method of any one of claims 37 to 61,wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered in anextended release form, a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form.
 63. The method of any one of claims 37 to 61, wherein theSV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof is administered in a form that isnot an extended release form, a controlled release form, a prolongedrelease form, a sustained release form, a delayed release form, or aslow release form.
 64. The method of any one of claims 37 to 63, whereinthe valproate or the derivative, analog, pharmaceutically acceptablesalt, hydrate, solvate, polymorph or prodrug thereof is administered inan extended release form, a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form.
 65. The method of any one of claims 37 to 63, wherein thevalproate or the derivative, analog, pharmaceutically acceptable salt,hydrate, solvate, polymorph or prodrug thereof is administered in a formthat is not an extended release form, a controlled release form, aprolonged release form, a sustained release form, a delayed releaseform, or a slow release form.
 66. A pharmaceutical compositioncomprising an SV2A inhibitor or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof, the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof being present in an amount of 5-140 mg.
 67. Apharmaceutical composition comprising an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof, the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof being present inan amount of 0.7-200 mg.
 68. A pharmaceutical composition comprising anSV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof being present in an amount of 0.07-350 mg.
 69. Apharmaceutical composition comprising an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof, the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof being present inan amount of 50-250 mg.
 70. A pharmaceutical composition comprising anSV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof being present in an amount of 3-50 mg.
 71. Apharmaceutical composition comprising an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof, the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof being present inan amount of 0.05-35 mg.
 72. A pharmaceutical composition comprising anSV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof, the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof being present in an amount of 0.1-500 mg.
 73. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 0.1-350 mg.
 74. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 0.7-350 mg.
 75. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 3-300 mg.
 76. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 3-150 mg.
 77. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 3-110 mg.
 78. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 7-70 mg.
 79. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 70-350 mg.
 80. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 100-300 mg.
 81. Thepharmaceutical composition of claim 72, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount of 125-250 mg.
 82. Thepharmaceutical composition of any one of claims 66-81, wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is in an extended release form, acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form.
 83. Apharmaceutical composition comprising an SV2A inhibitor or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof and valproate or a derivative, analog, pharmaceuticallyacceptable salt, hydrate, solvate, polymorph or prodrug thereof.
 84. Thepharmaceutical composition of claim 83, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in the composition is present in an amount of 0.05-35mg.
 85. The pharmaceutical composition of claim 83, wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in the composition is present in an amountof 0.07-350 mg.
 86. The pharmaceutical composition of claim 83, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof in the composition is present inan amount of 50-250 mg.
 87. The pharmaceutical composition of claim 83,wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in the composition ispresent in an amount of 3-50 mg.
 88. The pharmaceutical composition ofclaim 83, wherein the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof in the compositionis present in an amount of 0.07-50 mg.
 89. The pharmaceuticalcomposition of claim 83, wherein the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is present in an amount less than 500 mg, less than 350mg, less than 300 mg, less than 250 mg, less than 200 mg, less than 150mg, less than 110 mg, less than 100 mg, less than 70 mg, less than 50mg, less than 35 mg, less than 10 mg, less than 7 mg, less than 5 mg,less than 3 mg, less than 1 mg, less than 0.7 mg, less than 0.5 mg, lessthan 0.1 mg, less than 0.07 mg, or less than 0.05 mg.
 90. Thepharmaceutical composition of claim 83, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in the composition is present in an amount of 0.1-500mg.
 91. The pharmaceutical composition of claim 83, wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in the composition is present in an amountof 0.1-350 mg.
 92. The pharmaceutical composition of claim 83, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof in the composition is present inan amount of 0.7-350 mg.
 93. The pharmaceutical composition of claim 83,wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in the composition ispresent in an amount of 3-300 mg.
 94. The pharmaceutical composition ofclaim 83, wherein the SV2A inhibitor or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof in the compositionis present in an amount of 3-150 mg.
 95. The pharmaceutical compositionof claim 83, wherein the SV2A inhibitor or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof in thecomposition is present in an amount of 3-110 mg.
 96. The pharmaceuticalcomposition of claim 83, wherein the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof in the composition is present in an amount of 7-70 mg.97. The pharmaceutical composition of claim 83, wherein the SV2Ainhibitor or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof in the composition is present in an amountof 70-350 mg.
 98. The pharmaceutical composition of claim 83, whereinthe SV2A inhibitor or the pharmaceutically acceptable salt, hydrate,solvate, polymorph, or prodrug thereof in the composition is present inan amount of 100-300 mg.
 99. The pharmaceutical composition of claim 83,wherein the SV2A inhibitor or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof in the composition ispresent in an amount of 125-250 mg.
 100. The pharmaceutical compositionof any one of claims 83-99, wherein the SV2A inhibitor or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in an extended release form, a controlled releaseform, a prolonged release form, a sustained release form, a delayedrelease form, or a slow release form.
 101. The pharmaceuticalcomposition of any one of claims 83-99, wherein the SV2A inhibitor orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is in a form that is not an extended release form, acontrolled release form, a prolonged release form, a sustained releaseform, a delayed release form, or a slow release form.
 102. Thepharmaceutical composition of any one of claims 83-100, wherein thevalproate or the derivative, analog, pharmaceutically acceptable salt,hydrate, solvate, polymorph or prodrug thereof is in an extended releaseform, a controlled release form, a prolonged release form, a sustainedrelease form, a delayed release form, or a slow release form.
 103. Thepharmaceutical composition of any one of claims 83-100, wherein thevalproate or the derivative, analog, pharmaceutically acceptable salt,hydrate, solvate, polymorph or prodrug thereof is in a form that is notan extended release form, a controlled release form, a prolonged releaseform, a sustained release form, a delayed release form, or a slowrelease form.
 104. A method for treating cognitive impairment associatedwith a central nervous system (CNS) disorder in a subject in need or atrisk thereof, delaying or slowing the progression of cognitiveimpairment in the subject, or reducing the rate of decline of cognitivefunction in the subject, the method comprising the step of administeringto said subject a therapeutically effective amount of levetiracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof.
 105. The method of claim 104, wherein the levetiracetamor the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 1-2 mg/kg.
 106. Themethod of claim 104, wherein the levetiracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 70-140 mg.
 107. The method of claim 104,wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 0.1-2.5 mg/kg.
 108. The method of claim 104, wherein thelevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 7-200mg.
 109. The method of claim 104, wherein the levetiracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 0.4-2.5 mg/kg. 110.The method of claim 104, wherein the levetiracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 25-200 mg.
 111. The method of claim 104,wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 0.6-1.5 mg/kg.
 112. The method of claim 104, wherein thelevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 40-130mg.
 113. The method of claim 104, wherein the levetiracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 2.0-4.0 mg/kg. 114.The method of claim 104, wherein the levetiracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 140-300 mg.
 115. The method of claim104, wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 3.0-4.0 mg/kg.
 116. The method of claim 104, wherein thelevetiracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 200-300mg.
 117. The method of claim 104, wherein the levetiracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 2.0-3.0 mg/kg. 118.The method of claim 104, wherein the levetiracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 140-200 mg.
 119. The method of claim104, wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose according to Table 1 or Table
 2. 120. The method of claim104, wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 0.1-5 mg/kg or 7-350 mg.
 121. The method of claim 104,wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 1-5 mg/kg or 70 mg-350 mg.
 122. The method of claim 104,wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 1.5-4 mg/kg or 100 mg-300 mg.
 123. The method of claim104, wherein the levetiracetam or a pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 1.5-3.6 mg/kg or 125 mg-250 mg.
 124. The method of any oneof claims 104-123, wherein the levetiracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered in an extended release form, a controlled release form, aprolonged release form, a sustained release form, a delayed releaseform, or a slow release form.
 125. The method of any one of claims104-124, wherein the levetiracetam or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof is administeredonce daily.
 126. The method of any one of claims 104-123, wherein thelevetiracetam or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered twice daily.
 127. A methodfor treating cognitive impairment associated with a central nervoussystem (CNS) disorder in a subject in need or at risk thereof, delayingor slowing the progression of cognitive impairment in the subject, orreducing the rate of decline of cognitive function in the subject, themethod comprising the step of administering to said subject atherapeutically effective amount of brivaracetam or a pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof. 128.The method of claim 127, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 0.1-0.2 mg/kg. 129.The method of claim 127, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 7-15 mg.
 130. Themethod of claim 127, wherein the brivaracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.01-2.5 mg/kg.
 131. The method of claim127, wherein the brivaracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 0.7-200 mg.
 132. The method of claim 127, wherein thebrivaracetam or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of0.04-2.5 mg/kg.
 133. The method of claim 127, wherein the brivaracetamor the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 2.5-200 mg.
 134. Themethod of claim 127, wherein the brivaracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.06-1.5 mg/kg.
 135. The method of claim127, wherein the brivaracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 4.0-130 mg.
 136. The method of claim 127, wherein thebrivaracetam or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 0.2-0.4mg/kg.
 137. The method of claim 127, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 14-30 mg.
 138. Themethod of claim 127, wherein the brivaracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of 0.1-35 mg or 0.0015-0.5 mg/kg.
 139. Themethod of claim 127, wherein the brivaracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered at a daily dose of at least 0.1 mg, 0.5 mg, 0.75 mg, 1.0mg, 1.5 mg, or 2.0 mg; and at a daily dose of no more than 2.5 mg, 5 mg,10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg.
 140. The method of claim127, wherein the brivaracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of at least 0.0015 mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015mg/kg, 0.02 mg/kg, or 0.03 mg/kg; and at a daily dose of no more than0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05mg/kg, or 0.04 mg/kg.
 141. The method of claim 127, wherein thebrivaracetam or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose accordingto Tables 3-6.
 142. The method of claim 127, wherein the brivaracetam orthe pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 0.1-350 mg or0.0015-5 mg/kg.
 143. The method of claim 127, wherein the brivaracetamor the pharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 0.7-350 mg or 0.01-5mg/kg.
 144. The method of claim 127, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 3-300 mg or 0.05-4mg/kg.
 145. The method of claim 127, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 3-150 mg or 0.05-2mg/kg.
 146. The method of claim 127, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 3-110 mg or 0.05-1.5mg/kg.
 147. The method of claim 127, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of 7-70 mg or 0.1-1mg/kg.
 148. The method of any one of claims 127-147, wherein thebrivaracetam or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered in an extended releaseform, a controlled release form, a prolonged release form, a sustainedrelease form, a delayed release form, or a slow release form.
 149. Themethod of any one of claims 127-147, wherein the brivaracetam or thepharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered twice daily.
 150. The method of any oneof claims 127-148, wherein the brivaracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered once daily.
 151. A method for treating cognitive impairmentassociated with a central nervous system (CNS) disorder in a subject inneed or at risk thereof, delaying or slowing the progression ofcognitive impairment in the subject, or reducing the rate of decline ofcognitive function in the subject, the method comprising the step ofadministering to said subject a therapeutically effective amount ofseletracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof.
 152. The method of claim 151, wherein theseletracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of 0.1-35mg or 0.0015-0.5 mg/kg.
 153. The method of claim 151, wherein theseletracetam or a pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered at a daily dose of atleast 0.1 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, or 2.0 mg; and at a dailydose of no more than 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or35 mg.
 154. The method of claim 151, wherein the seletracetam or apharmaceutically acceptable salt, hydrate, solvate, polymorph, orprodrug thereof is administered at a daily dose of at least 0.0015mg/kg, 0.0075 mg/kg, 0.01 mg/kg, 0.015 mg/kg, 0.02 mg/kg, or 0.03 mg/kg;and at a daily dose of no more than 0.5 mg/kg, 0.4 mg/kg, 0.3 mg/kg, 0.2mg/kg, 0.15 mg/kg, 0.1 mg/kg, 0.05 mg/kg, or 0.04 mg/kg.
 155. The methodof claim 151, wherein the seletracetam or a pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof is administered ata daily dose according to Tables 7-10.
 156. The method of claim 151,wherein the seletracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 0.1-350 mg or 0.0015-5 mg/kg.
 157. The method of claim151, wherein the seletracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 0.7-350 mg or 0.01-5 mg/kg.
 158. The method of claim 151,wherein the seletracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 3-300 mg or 0.05-4 mg/kg.
 159. The method of claim 151,wherein the seletracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 3-150 mg or 0.05-2 mg/kg.
 160. The method of claim 151,wherein the seletracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 3-110 mg or 0.05-1.5 mg/kg.
 161. The method of claim 151,wherein the seletracetam or the pharmaceutically acceptable salt,hydrate, solvate, polymorph, or prodrug thereof is administered at adaily dose of 7-70 mg or 0.1-1 mg/kg.
 162. The method of any one ofclaims 151-161, wherein the seletracetam or the pharmaceuticallyacceptable salt, hydrate, solvate, polymorph, or prodrug thereof isadministered in an extended release form, a controlled release form, aprolonged release form, a sustained release form, a delayed releaseform, or a slow release form.
 163. The method of any one of claims151-161, wherein the seletracetam or the pharmaceutically acceptablesalt, hydrate, solvate, polymorph, or prodrug thereof is administeredtwice daily.
 164. The method of any one of claims 151-162, wherein theseletracetam or the pharmaceutically acceptable salt, hydrate, solvate,polymorph, or prodrug thereof is administered once daily.
 165. Themethod of any one of claims 1-65 and 104-164, wherein the cognitiveimpairment is associated with age-related cognitive impairment.
 166. Themethod of claim 165, wherein the age-related cognitive impairment isMild Cognitive Impairment.
 167. The method of claim 166, wherein theMild Cognitive Impairment is amnestic Mild Cognitive Impairment. 168.The method of any one of claims 1-65 and 104-164, wherein the cognitiveimpairment is associated with dementia.
 169. The method of claim 168,wherein the dementia is Alzheimer's disease.
 170. The method of any oneof claims 1-65 and 104-164, wherein the cognitive impairment isassociated with schizophrenia.
 171. The method of any one of claims 1-65and 104-164, wherein the cognitive impairment is associated withamyotrophic lateral sclerosis.
 172. The method of any one of claims 1-65and 104-164, wherein the cognitive impairment is associated with posttraumatic stress disorder.
 173. The method of any one of claims 1-65 and104-164, wherein the cognitive impairment is associated with cancertherapy.
 174. The method of any one of claims 1-65 and 104-164, whereinthe cognitive impairment is associated with bipolar disorder.
 175. Themethod of any one of claims 1-65 and 104-164, wherein the cognitiveimpairment is associated with mental retardation.
 176. The method of anyone of claims 1-65 and 104-164, wherein the cognitive impairment isassociated with Parkinson's disease.
 177. The method of any one ofclaims 1-65 and 104-164, wherein the cognitive impairment is associatedwith autism.
 178. The method of any one of claims 1-65 and 104-164,wherein the cognitive impairment is associated with compulsive behavior.179. The method of any one of claims 1-65 and 104-164, wherein thecognitive impairment is associated with substance addiction.
 180. Themethod of any one of claims 1-65 and 104-164, wherein the effect of thetreatment, the progression of cognitive impairment, or the rate ofdecline of cognitive function is measured by the Clinical DementiaRating Scale.
 181. The method of any one of claims 1-65 and 104-164,wherein the effect of the treatment, the progression of cognitiveimpairment, or the rate of decline of cognitive function is measured bydetecting the difference between the levels of reelin in the subjectprior to and after the administration step.
 182. The method of any oneof claims 1-65 and 104-164, wherein the effect of the treatment, theprogression of cognitive impairment, or the rate of decline of cognitivefunction is measured by detecting the difference between the levels ofsomatostatin in the subject prior to and after the administration step.